Method and apparatus for delivery of therapeutic agents

ABSTRACT

Methods and apparatus for the reproducible, consistent and efficacious delivery of a therapeutic agent to a subject. The present disclosure comprises apparatus for the controlled administration of the therapeutic agent through an orifice to the subject, a plurality of penetrating electrodes arranged with a predetermined spatial relationship relative to the orifice, and an electrical signal generator operatively connected to the electrodes.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the benefit of U.S. provisional PatentApplication No. 62/314,286, filed Mar. 28, 2016, which is herebyincorporated by reference in its entirety.

FIELD

The present disclosure is directed to the administration of prophylacticand therapeutic agents to patients and, more particularly, to thereproducible, consistent, and efficacious delivery of prophylactic andtherapeutic agents, such as nucleic acids, drugs, peptides, and proteinsor combinations thereof, to defined regions in selected tissues ofinterest, facilitated by the local application of electrical fields, ina safe, effective, and consistent fashion across heterogeneous recipientpopulations with minimal user training.

BACKGROUND

Prophylactic and therapeutic agents have long been delivered to patientsusing various conventional routes of administration, such as topical,oral, intravenous, parenteral, and the like. Once administered to thepatient by the selected route, the delivery of the agent to the tissueof interest and its beneficial interaction with the tissue is largelydependent on its inherent physicochemical factors, but may befacilitated by, for example, selected components of the deliverycomposition such as carriers, adjuvants, buffers and excipients, and thelike.

The local application of electrical signals has been shown to enhancethe distribution and uptake of macromolecules in living tissue.Application of such electrical signals in tissue in association with theadministration of a prophylactic or therapeutic agent can have desirableeffects on the tissue and/or the agent to be delivered. Specifically,techniques such as electroporation and iontophoresis have been utilizedto significantly improve the distribution and/or uptake of a variety ofagents in tissue. Such agents include pharmaceuticals, proteins,peptides, and nucleic acids, including both DNA and RNA sequences.Potential clinical applications of such techniques include the deliveryof chemotherapeutic drugs in tumors, the delivery of nucleic acidsequences for prophylactic and therapeutic immunization, and thedelivery of nucleic acid sequences encoding therapeutic proteins orpeptides.

Many devices have been described for the application of electricalsignals in tissue for the purpose of enhancing agent delivery. Themajority of these have focused on a means for effective application ofthe electrical signals within a target region of tissue. A variety ofsurface and penetrating electrode systems have been developed forgenerating the desired electrophysiological effects.

These procedures comprise the administration of an agent of interest toa target tissue site in conjunction with the application of electricalfields of sufficient magnitude and duration to induce the desiredeffects on the delivery, distribution, and/or potency of the agent. Theelectrical fields are propagated via two or more electrodes inelectrically conductive communication with the tissue. Electrodeconfigurations suitable for use with these techniques include tissuepenetrating electrodes, surface contact electrodes, and air gapelectrodes. Specific electrode configurations include, but are notlimited to, elongate needle or rod electrodes, point electrodes, meanderelectrodes (i.e., shaped wire), planar electrodes, and combinationsthereof. The specific type and arrangement of electrodes is selectedbased on the target tissue type and the objectives of the procedure.

An important consideration for the use of with these techniques is thatenhancement of agent activity is contingent on achieving spatial andtemporal co-localization of the agent of interest with the electricalfield. Specifically, the desired outcome is best achieved when theelectrical fields are propagated within the target tissue in thepresence of the agent of interest.

A broad range of methods and devices have been described for theapplication of electrical fields in tissue in the presence of an agentof interest for the purpose of enhancing agent delivery in skin andmuscle tissue. The devices include the use of both surface and tissuepenetrating electrode systems as well as combinations thereof. In spiteof the promise associated with electrically mediated agent delivery andthe potential clinical applications of these techniques, progress hasbeen hampered by the lack of an effective means to achieve the overallobjective of efficient and reliable agent delivery using thesetechniques. One of the most significant shortcomings of current systemsis the inability to achieve reliable and consistent application fromsubject to subject. Significant sources of this variability are due todifferences in the technique and skill level of the operator. Othersources of variability that are not addressed by current systems includedifferences in the physiologic characteristics between patients that canaffect the application of the procedure. Other considerations for thedevelopment of suitable devices include their ease of use and theimplementation of designs that reduce the frequency and significance ofpotential user errors.

Given that safe, reliable, accurate, and consistent application ofclinical therapies is highly desirable, the development of improvedapplication systems is well warranted. Such development should include ameans for minimizing operator-associated variability while providing ameans to accommodate the differences in patient characteristics likelyto be encountered during widespread clinical application of electricallymediated agent delivery. In other words, specific areas for refinementinclude the ability to maintain consistent performance acrossheterogeneous recipient populations and a reduction in the level oftraining and skill required for effective use by the user. In addition,the device should be designed to facilitate avoidance of user or deviceerrors and minimize their impact when they occur.

This Background is provided to introduce a brief context for the Summaryand Detailed Description that follow. This Background is not intended tobe an aid in determining the scope of the claimed subject matter nor beviewed as limiting the claimed subject matter to implementations thatsolve any or all of the disadvantages or problems presented above.

SUMMARY OF THE DISCLOSURE

The present disclosure provides methods and apparatus for thereproducible, consistent, and efficacious delivery of therapeuticagents, such as nucleic acids, pharmaceutical drugs, peptides, andproteins or combinations thereof, to patients or subjects utilizingElectrically Mediated Therapeutic Agent Delivery (EMTAD). As usedherein, a patient is alterntaively called a subject, and vice-versa. Useof the term “patient” does not require that the subject be under adoctor's care, althouth they may be.

In one aspect, provided is an apparatus for the delivery of atherapeutic agent to a predetermined site within a patient or subjectcomprising an assembly for controlled administration of the therapeuticagent to the subject comprising a reservoir for the therapeutic agent,at least one orifice through which the agent is administered, and acontrolled source of energy sufficient to transfer a predeterminedamount of the therapeutic agent at a predetermined rate from thereservoir through the orifice to the predetermined site within thesubject. In addition, the apparatus can comprise a plurality ofpenetrating electrodes arranged with a predetermined spatialrelationship relative to the orifice, and means for generating anelectrical signal operatively connected to the electrodes.

Other aspects of the present disclosure include methods comprisingTherapeutic Agent Administration (TEA) in controlled spatial andtemporal relation with Electric Signal Administration (ESA).

Benefits and advantages to certain implementations according to presentprinciples are manifold. Some implementations allow the selection ofdepth of needle and electrode insertion, allowing insertion into varioustypes of desired tissue, (e.g., dermis, muscle, etc.) acrossheterogeneous populations of varying body mass and body composition.These implementations also facilitate adaptation of the methods for usein specific target populations, for instance, but not restricted to, menfor cancer therapeutic agents such as prostate cancer therapeuticagents, individuals for vaccination and/or treatment such as pregnantwomen for Zika virus vaccination or treatment, small children forpediatric vaccines including cancer vaccines, and so on. Provided hereinare systems and methods comprising design features render the systemsand methods resistant to accidental discharge or potential misuse, e.g.,due to dropping, jarring, and/or falling. In some embodiments areprovided devices configured for multiple injection depths. Systems andmethods according to present principles allow numerous safety interlocksto reduce the frequency and/or impact of user errors. These includefeatures to facilitate proper preparation and configuration of the doseto be administered, ensuring that the device is applied with requisiteforce to the tissue of the recipient, ensuring that a safety cap hasbeen removed, and so on. Systems, apparatus and methods according topresent principles can allow for a highly consistent therapy to bedelivered irrespective of administrator or the type of recipient.Systems, apparatus and methods described herein can allow for, e.g., aconsistent force profile to be obtained prior to and during delivery ofthe therapy, so that recipients with varying skin and muscularcharacteristics can be dosed consistently.

Provided herein is an apparatus for the controlled delivery of atherapeutic agent to a predetermined tissue site within a subjectcomprising: a cartridge assembly comprising an outer cartridge, an innercartridge, a needle hub, a vessel configured to contain the therapeuticagent, wherein the outer cartridge provides a vessel receiver configuredto receive the vessel; an applicator comprising a cartridge assemblyreceiver configured to receive the cartridge assembly or a portionthereof, and an insertion detector, wherein the insertion detector isconfigured to sense loading of the vessel in the vessel receiver; avessel interlock, wherein the vessel interlock is configured to lock outthe apparatus from actuation until the vessel is loaded properly in thevessel receiver; at least one injection orifice in fluid communicationwith the therapeutic agent when the agent is loaded in the vessel andthrough which the therapeutic agent is administered; a plurality ofpenetrating electrodes arranged with a predetermined spatialrelationship relative to the orifice; an electrical field generatorconfigured to generate an electrical signal operatively connected to theelectrodes; and a controlled source of energy sufficient to transfer apredetermined amount of the therapeutic agent at a predetermined ratefrom the vessel through the orifice to the predetermined site within thesubject.

In some embodiments, the apparatus further comprises a needle. In someemdociments, the electrodes are a plurality of elongate electrodes. Inanother embodiment, the vessel interlock is configured to preventinadvertent actuation of cartridge function. The vessel interlock maycomprise a mechanical interlock. In some embodiments, the apparatuscomprises a second interlock comprising a light emitter/collector, acartridge breech, a force interlock, an alignment guide and a splayshield, a trigger lock, a safety switch, an exterior cartridge cap or acombination thereof. In certain embodiments, the mechanical interlockcomprises tabs that are moved from a first position to a second positionby the vessel when the vessel is properly loaded, whereby when the tabsare in the second position, the device may be actuated. In anotherembodiment, the vessel interlock further comprises at least one vessellockout hole. In yet another embodiment, the cartridge breech providesan optical line of sight through a vessel lockout hole. It yet anotherembodiment, the a vessel detection cap may engage the cartridge breechthrough a vessel detection spring. In some embodiments, the vesseldetection spring is configured to push the reservoir into engagementwith the needle hub. In some embodiments, the vessel interlock furthercomprises a tab extending from a cartridge surface, and wherein the tabis configured to interact with a corresponding detent feature located inthe applicator such that loading of the cartridge into the applicator isphysically blocked unless the tab is deflected by a properly loadedvessel.

In some embodiments, the first interlock comprises a splay shield,wherein said exterior cartridge cap comprises an inner surface proximalto said splay shield, and wherein said inner surface further comprisesat least one hook capable of engaging a corresponding wall defined onsaid splay shield. In certain instances, the apparatus further comprisea third interlock. In another instance, the third interlock is a forceinterlock. In yet another instance, the force interlock senses a forceapplied against the predetermined tissue site of the subject andprevents administration of the therapeutic agent to the subject wheninsufficient force is applied. In some embodiments, the force interlockfurther forms an electrical lock within the applicator. The forceinterlock may further comprise at least one cartridge force sensorcontact.

In some instances, the apparatus provided herein further comprises a keyto the vessel, wherein the key is configured to slides over a barrel ofthe vessel to ensure appropriate mating within the cartridge assembly.In certain instances, the first interlock comprises a splay shield thatcomprises a rib and an edge configured to engage with the predeterminedtissue site of the subject and configured to place the apparatus intotension perpendicular to the direction of the needle deployment foradministration of the therapeutic agent. The first interlock of theapparatus provided herein may comprise a splay shield which comprises aforce contact pick up. The force contact pick up may comprise at leastone first pad, at least one second pad, and a flexible circuit. In someembodiments, the first interlock further comprises a splay shield, andsaid splay shield is mechanically biased by at least one force contactspring.

The cartridge assembly of the apparatus as provided herein may furthercomprise a stick shield. In some embodiments, the stick shield furthercomprises a stick shield nub, a stick shield hole, and a stick shieldspring. In some embodiments, the first interlock comprises the splayshield that comprises at least one hole for slidable movement of thestick shield. In certain embodiments, the apparatus provided hereinfurther comprises at least one stick shield support to interface withthe outer cartridge. In an exemplary embodiment, the stick shieldsupport is a stamped metal support arm. In another exemplary embodiment,the stick shield supports moves over at least one retaining wall in asequential order. In some embodiments, the apparatus provided hereincomprises a first retaining wall which can prevent proximal movement ofthe stick shield in case of discharge of said apparatus at a firstselected depth and a second retaining wall which can prevent proximalmovement of the stick shield after discharge of said apparatus at asecond selected depth in a subject. In some embodiments, the stickshield support is integrated as an injection molded plastic feature ofan outer cartridge cap.

In another embodiment, the stick shield support abuts the stick shieldand prevents the stick shield from moving in the proximal direction in aratcheting fashion. In yet another embodiment, the apparatus as providedherein further comprises a gear rack implemented on the stick shield toreduce proximal movement. In certain cases, the stick shield supportprevents the stick shield from moving in the proximal direction when atleast 5 N of force is applied. In another case, the stick shield supportprevents the stick shield from moving in the proximal direction when atleast 15 N of force is applied. In some cases, the stick shield supportis integrated as an injection molded plastic feature of the alignmentguide and splay shield. In some embodiments, wherein upon loading of thecartridge assembly into the applicator, the vessel moves forward to matewith the needle hub and contacts the cartridge to the needle at the timeof administration of the therapeutic agent. In another embodiment, theinner cartridge moves in a slidable manner in relationship to the outercartridge along a common longitudinal axis. In some instances, the innercartridge engages with an inner cartridge cap at a distal end, whereinthe inner cartridge cap locks the electrodes in place and provides abearing surface for the stick shield.

The apparatus as provided here in may further comprises a sensor. Insome embodiments, the sensor is selected from the group consisting of acartridge loading sensor, a cartridge loaded sensor, a cartridge forcesensor, an insertion mechanism position sensor, the insertion detector,an optical detector, and an electrical sensor. In some embodiments, aloading drive subassembly comprises a cartridge loading sensor and acartridge loaded sensor. In some embodiments, the loading drivesubassembly further comprises at least one cartridge guide rail and aloading motor. In some embodiments, the loading drive subassemblyfurther comprises a connection to a pinion gear assembly pulling thecartridge assembly into the cartridge assembly receiver via a rack on abase of the outer cartridge. In some embodiments, the pinion gearassembly engages the rack on the outer cartridge. In some embodiments,the rack comprises at least a first rack tooth. In some embodiments, thefirst rack tooth provides a tactile sensation when the cartridgeassembly is inserted into the cartridge assembly receiving volume. Insome embodiments, the first rack tooth provides torsional stability. Insome embodiments, the cartridge loading sensor detects an initiatingflag on the cartridge assembly to initiate loading. In some embodiments,the cartridge loaded sensor detects an initiating flag on the cartridgeassembly to cease loading. In certain embodiments, the apparatus furthercomprises a continuing flag for the cartridge loading to continue. Insome embodiments, the apparatus further comprises an insertion detectorthat comprises a light emitter/collector IR sensor. In some embodiments,the sensor detects a vessel label and verifies the therapeutic agent.

Provided herein is an apparatus for the controlled delivery of atherapeutic agent to a predetermined tissue site within a subjectcomprising: a cartridge assembly comprising a housing, a needle hub, avessel configured to contain the therapeutic agent, wherein the housingcomprises a vessel receiver configured to receive the vessel; anapplicator comprising a cartridge assembly receiver, and an insertiondetector, wherein the insertion detector is configured to sense loadingof the vessel in the vessel receiver; and at least one injection orificeof an injection needle through which the therapeutic agent isadministered; a plurality of penetrating electrodes arranged with apredetermined spatial relationship relative to the orifice; an electrodesupport comprising a plurality of apertures corresponding to thepredetermined special relationship of the electrodes and through whichthe electrodes extend, wherein the electrode support structure preventsinadvertent perpendicular motion of the electrodes relative to thedirection of electrode deployment; an electrical field generatorconfigured to generate an electrical signal that is operativelyconnected to the electrodes; and a controlled source of energysufficient to transfer a predetermined amount of the therapeutic agentat a predetermined rate from the reservoir through the orifice to thepredetermined site within the subject.

In some embodiments, the apparatus further comprises a needle. In someembodiments, the apparatus further comprises an electrode insertionspring or a needle insertion spring. In some embodiments, the proximalportion of the electrode is separated from the distal portion of theelectrode by an electrode shoulder or an electrode bend. In someembodiments, the electrode support provides an operative connectionbetween a conductive contact region located on the distal region of theelectrodes and the controlled source of energy when the electrodes aredeployed into the predetermined tissue site within the subject. In someembodiments, the electrode support comprises a needle hole positioned toallow for passage of the injection needle therethrough. In someembodiments, the electrode support comprises a planar structurepositioned perpendicularly relative to the elongate orientation of theelectrodes. In some embodiments, the planar structure further comprisesan aperture which is a hole or a slot configured to allow passage of theelectrode therethrough to the predetermined tissue site. In someembodiments, the aperture comprises at least one tubular structurearranged perpendicularly to the planar structure. In some embodiments,the planar structure is oriented perpendicular to the longitudinal axesof the electrodes. In some embodiments, the electrode support is anadaptive electrode support. In some embodiments, the adaptive electrodesupport is a compression spring. In some embodiments, the compressionspring is made from a metal, a polymer or an elastomeric material. Insome embodiments, the electrode support comprises at least onetelescoping tube. In some embodiments, the electrode support furthercomprises a stick shield spring. In some embodiments, the electrodesupport further comprises at least one lateral support member attachedto the electrodes with at least one optional hinge feature. In someembodiments, the electrode support comprises a metal, a polymer, aceramic, a composite, or a compressible matrix material. In someembodiments, the compressible matrix material is selected from the groupconsisting of a cellulose, a foamed plastic, a rubber polymer, amicrocellular plastic, foamed silicon, foamed polychloroprene, carbonfoam matrix. In some embodiments, the electrode support is made from anunconducive material. In some embodiments, the electrode support is madeof a thermoplastic material. In some embodiments, the thermoplasticmaterial is selected from the group consisting of a polycarbonate,polystyrene, polypropylene, an acrylic, or a polyethylene.

In some embodiments, the electrode support supports transcutaneousdeployment of the electrode and maintains at tissue depths up to 60 mm.In some embodiments, an electrode proximal portion of each electrode iscoupled to or contacts an electrode contact, wherein each electrode ispositioned on the exterior of the inner cartridge of the cartridgeassembly, wherein the electrode contact is configured for powercommunication with corresponding connections on the applicator. In someembodiments, the electrode contact further comprises an outer cartridgeexterior contact. In some embodiments, the electrode contact provides anelectrically conductive interface with corresponding electrodes whilenot interfering with forward travel of the electrodes mounted on theinner cartridge. In some embodiments, the cartridge assembly furthercomprises a vessel loading port. In some embodiments, an outercartridge, said outer cartridge comprising an inner cartridgecontainment volume. In some embodiments, the applicator furthercomprises an injection drive assembly, wherein the injection driveassembly mates with the cartridge assembly. In some embodiments, theapplicator further comprises a an applicator cartridge assemblyreceiving port. In some embodiments, the applicator further comprises aa procedure activation trigger. In some embodiments, the applicatorfurther comprises a a connector for connection to the controller, a tophousing, a side housing, and an inner protective shell. In someembodiments, the vessel further comprises a vessel cap. In someembodiments, the apparatus further comprises an egress port. In someembodiments, the apparatus further comprises a plunger stopper. In someembodiments, the apparatus further comprises a multiconductor cable. Insome embodiments, the apparatus further comprises an exterior cartridgecap chamfer surface. In some embodiments, the apparatus furthercomprises an exterior cartridge cap hook. In some embodiments, theapparatus further comprises a main power port. In some embodiments, theapparatus further comprises a main power switch, a power button, and apower indicator. In some embodiments, the apparatus further comprises aat least one connector for switch.

Provided herein are embodiments wherein an apparatus described hereincomprises a hybrid motor/spring mechanism for contacting at least one ofsaid injection orifice or said plurality of electrodes with saidpredetermined tissue site.

In some embodiments, the apparatus further comprises a at least oneconnector for switch. In some embodiments, the apparatus furthercomprises an USB port. In some embodiments, the apparatus furthercomprises a reminder tab. In some embodiments, the apparatus furthercomprises a battery indicator. In some embodiments, the apparatusfurther comprises a mute button. In some embodiments, the apparatusfurther comprises at least one menu navigation button. In someembodiments, the apparatus further comprises an eject cartridge button.In some embodiments, the apparatus further comprises a display screen.In some embodiments, the apparatus further comprises a tray. In someembodiments, the apparatus further comprises an applicator connectorport. In some embodiments, the apparatus further comprises an applicatorcradle. In some embodiments, the apparatus further comprises a cradle.In some embodiments, the apparatus further comprises a storage bin. Insome embodiments, the apparatus further comprises a handle. In someembodiments, the apparatus further comprises a abutment wall. In someembodiments, the apparatus further comprises at least one applicatorelectroporation electrode contact. In some embodiments, the apparatusfurther comprises at least one electrical connector. In someembodiments, the apparatus further comprises a cartridge loadingsubassembly. In some embodiments, the apparatus further comprises amotor drive and at least one electrical contact for motor drive. In someembodiments, the apparatus further comprises a loading drive motor. Insome embodiments, the apparatus further comprises a motor triggerconnector. In some embodiments, the apparatus further comprises a motordrive shaft. In some embodiments, the apparatus further comprises atleast one electromechanical subassembly. In some embodiments, theapparatus further comprises at least one cartridge loading, electrodeinsertion, and injection subassembly. In some embodiments, the apparatusfurther comprises at least one injection depth selection button and aninjection depth selection indicator. In some embodiments, the apparatusfurther comprises a procedure countdown timer. In some embodiments, theapparatus further comprises at least one gear cover bracket and at leastone mounting bracket.

In some embodiments, the apparatus further comprises a system triggerswitch. In some embodiments, the apparatus further comprises a systemtrigger switch. In some embodiments, the apparatus further comprises aprocedure fault indicator and a procedure complete indicator. In someembodiments, the apparatus further comprises a depth selection button.In some embodiments, the depth selection button is selected from thegroup consisting of a toggle, a switch, and a sliding switch. In someembodiments, the apparatus further comprises a plurality of channel anda plurality of retaining post. In some embodiments, the apparatusfurther comprises an insertion mechanism gear drive ring and aninsertion gear ring. In some embodiments, rotation of the insertionmechanism gear ring rotates the retaining post into the channel.

In some embodiments, the apparatus further comprises an insertionmechanism flag, an insertion mechanism drive motor, an insertionmechanism position sensor, an injection drive plunger, an injectiondrive motor, or an injection drive gearing. In some embodiments, theapparatus further comprises a cartridge lock ring. In some embodiments,the rotation of the cartridge lock ring rotates the retaining posts. Insome embodiments, the cartridge assembly is for single use. In someembodiments, the applicator is for multiple uses. In some embodiments,the applicator further comprises a top housing, a side housing, an innerprotective shell, a front cap, and an end cap. In some embodiments, theapplicator further comprises a user interface, a procedure activationtrigger, a procedure countdown timer, a procedure fault indicator, or anapplication placement indicator. In some embodiments, the apparatusfurther comprises a controller. In some embodiments, the controllercomprises a controller assembly. In some embodiments, the applicatorfurther comprises a connector for connection to the controller. In someembodiments, the controller further comprises an electrical fieldcontroller.

In some embodiments, the penetrating electrodes and/or the injectionneedle come in contact with the predetermined tissue site with velocityof at least 50 mm/second. In some embodiments, the penetratingelectrodes and/or the injection needle come in contact with thepredetermined tissue site with velocity of at least 500 mm/second. Insome embodiments, the therapeutic agent is a nucleic acid. In someembodiments, the nucleic acid is DNA. In some embodiments, thepredetermined tissue site is located in a skeletal muscle of thesubject. In some embodiments, the skeletal muscle of the subject ismedial deltoid muscle or vastus lateralis muscle. In some embodiments,an injection depth at medial deltoid muscle is about 19-30 mm. In someembodiments, an injection depth at vastus lateralis muscle is about25-38 mm.

In some embodiments is provided an apparatus comprising a hybridmotor/spring mechanism for contacting at least one of said injectionorifice or said plurality of electrodes with said predetermined tissuesite. In some cases, the apparatus further comprises a measurement andlogic circuit to monitor the current usage of motor during the injectionstroke and compare said usage to a predetermined standard.

Provided is an apparatus described herein, further comprising acontroller and a force contact circuit wherein a feedback loop existsbetween said controller and said force contact circuit such that uponinsertion of said plurality of electrodes in said predetermined tissuesite, detection of a change in an applied force prompts initiation of acheck as to whether the electrodes remain properly deployed in saidpredetermined tissue site.

In some cases is an apparatus described herein wherein the plurality ofelectrodes and/or one or more needle are deployed by rotational motion.

Provided is a method of providing a therapeutic agent to a predeterminedtissue site in a subject in need thereof, comprising contacting saidsubject with an apparatus described herein. Provided are systems forproviding a therapeutic agent to a predetermined tissue site in asubject in need thereof, comprising an apparatus described herein.

This Summary is provided to introduce a selection of concepts in asimplified form. The concepts are further described in the DetailedDescription section. Elements or steps other than those described inthis Summary are possible, and no element or step is necessarilyrequired. This Summary is not intended to identify key features oressential features of the claimed subject matter, nor is it intended foruse as an aid in determining the scope of the claimed subject matter.The claimed subject matter is not limited to implementations that solveany or all disadvantages noted in any part of this disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The features of the present disclosure are set forth with particularityin the appended claims. A better understanding of the features andadvantages of the present disclosure will be obtained by reference tothe following detailed description that sets forth illustrativeembodiments, in which the principles of the disclosure are utilized, andthe accompanying drawings of which:

FIG. 1 illustrates potential sources of spatial variability associatedwith conventional needle syringe injection.

FIG. 2 is an overview of a system according to present principles,including a cartridge assembly 100, an applicator 400, and a controllersystem 700.

FIGS. 3A-3B show views of aspects of a device described herein. FIG. 3Ashows a lateral view of a cartridge assembly 100 according to presentprinciples. FIG. 3B shows a lateral view of a reservoir 101 embodied asa syringe, according to present principles.

FIG. 4 shows various exemplary components of a cartridge assembly 100according to present principles.

FIGS. 5A-5E show views of aspects of an inner cartridge and cartridgebreech in a device described herein. FIG. 5A illustrates a top view ofan inner cartridge 103 according to present principles. FIG. 5Billustrates a bottom view of an inner cartridge 103 and cartridge breechaccording to present principles. FIG. 5C illustrates a detail sideperspective view of an inner cartridge 103 according to presentprinciples. FIG. 5D shows a lateral view of a cartridge breech 112according to present principles. FIG. 5E illustrates vessel interlock120 with improved locking features to prevent the cartridge breech 112from inadvertently moving forward.

FIG. 6 illustrates details of a cartridge assembly showing a rack 154, ainitiating flag 172, and a continuing flag 174 according to presentprinciples.

FIGS. 7A-7B show views of aspects of electrodes and/or one or moreelectrode contact in a device described herein. FIG. 7A shows details ofone or more electrode contact 130 and various elecrode contact portionsaccording to present principles. FIG. 7B shows details of electrodes 122and various electrode contact portions according to present principles.

FIGS. 8A-8B show views of aspects of a force contact interlock system ina device described herein. FIG. 8A shows a top view of a force contactinterlock system according to the present principle. FIG. 8B illustratesdetails of a force contact interlock system according to presentprinciples.

FIGS. 9A-9D show views of aspects of a device described herein. FIG. 9Ashows a needle 105 and distal inner cartridge electrodes 137 for tissueinsertion according to present principles.

FIG. 9B illustrates details of a stick shield 134 according to presentprinciples. FIG. 9C illustrates an alignment guide 108 and splay shield168 according to present principles. FIG. 9D illustrates stick shieldsupports intergral to outer cartridge cap 106.

FIGS. 10A-10D show views of aspects of exterior cartridge cap in adevice described herein. FIG. 10A shows an exterior cartridge cap 110according to present principles. FIG. 10B shows a side view of anexterior cartridge cap 110 according to present principles. FIG. 10Cshows an exterior cartridge cap 110 in use in an alignment guide 108 andsplay shield according to present principles. FIG. 10D shows an exteriorcartridge cap 110 with extension members designed to hold the innercartridge 103 in place during handling and loading.

FIGS. 11A-11C show details of stick shields in aspects of a devicedescribed herein. FIG. 11A shows a stick shield retaining hook 182 of astick shield 134 according to present principles.

FIG. 11B shows details of a stick shield 134 according to presentprinciples. FIG. 11C shows stick shield supports 132 keeping a stickshield 134 in place according to present principles.

FIG. 12 shows details of an electrode support 124 according to presentprinciples.

FIGS. 13A-13B show views of an applicator in a device described herein.FIG. 13A shows side view of an applicator 400 according to presentprinciples. FIG. 13B shows top views of an applicator 400 according topresent principles.

FIG. 14 is an exploded view of an applicator 400 according to presentprinciples.

FIG. 15 shows details of a side housing and electroporation electrodeconnection 496 of an applicator 400 according to present principles.

FIG. 16 is an exploded view of an applicator according to presentprinciples, showing a cartridge loading subassembly 456.

FIGS. 17A-17B show views of an applicator in a device described herein.FIG. 17A is an exploded view of an applicator according to presentprinciples, showing a loading drive subassembly 454. FIG. 17B shows arack 154 in a loading drive subassembly 454 according to presentprinciples.

FIGS. 18A-18C show views of aspects of an applicator in a devicedescribed herein. FIG. 18A shows details of a cartridge loadingsubassembly 456 according to present principles, showing where theinsertion/injection drive assembly of the applicator mates with thecartridge assembly. FIG. 18B shows a cross-sectional view of a cartridgeassembly according to present principles, showing where theinsertion/injection drive assembly of the applicator mates with thecartridge assembly. FIG. 18C shows details of cartridge loading,electrode insertion, and injection subassemblies 452 of an applicator400 according to present principles.

FIG. 19 shows various components of a controller system according topresent principles.

FIGS. 20A-20D show views of a device described herein. FIG. 20A showsvarious components of a controller system according to presentprinciples. FIG. 20B shows details of an applicator connector port 708and a tray 710 of a controller system according to present principles.

FIG. 20C shows details of a stimulator display screen of a controllersystem according to present principles. FIG. 20D shows details of a rearview of a controller system according to the present principles.

FIG. 21 is a flowchart showing a method of operation according topresent principles.

Like reference numerals refer to like elements throughout. Elements arenot to scale unless otherwise noted.

DETAILED DESCRIPTION

The following description and examples illustrate embodiments of theinvention in detail. It is to be understood that this invention is notlimited to the particular embodiments described herein and as such canvary. Those of skill in the art will recognize that there are numerousvariations and modifications of this invention, which are encompassedwithin its scope.

All terms are intended to be understood as they would be understood by aperson skilled in the art. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which the disclosurepertains.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Although various features of the invention may be described in thecontext of a single embodiment, the features may also be providedseparately or in any suitable combination. Conversely, although theinvention may be described herein in the context of separate embodimentsfor clarity, the invention may also be implemented in a singleembodiment.

The following definitions supplement those in the art and are directedto the current application and are not to be imputed to any related orunrelated case, e.g., to any commonly owned patent or application.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice for testing of the presentdisclosure, the preferred materials and methods are described herein.Accordingly, the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting.

In this application, the use of the singular includes the plural unlessspecifically stated otherwise. It must be noted that, as used in thespecification, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

Reference in the specification to “some embodiments,” “an embodiment,”“one embodiment” or “other embodiments” means that a particular feature,structure, or characteristic described in connection with theembodiments is included in at least some embodiments, but notnecessarily all embodiments, of the inventions.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps. It is contemplated that any embodimentdiscussed in this specification can be implemented with respect to anymethod or composition of the invention, and vice versa. Furthermore,compositions of the invention can be used to achieve methods of theinvention.

The term “about” in relation to a reference numerical value and itsgrammatical equivalents as used herein can include the numerical valueitself and a range of values plus or minus 10% from that numericalvalue. For example, the amount “about 10” includes 10 and any amountsfrom 9 to 11. For example, the term “about” in relation to a referencenumerical value can also include a range of values plus or minus 10%,9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.

The present disclosure provides improved system, methods and apparatusfor the reproducible, consistent, and efficacious delivery oftherapeutic agents, such as nucleic acids, drugs, peptides, proteins andcombinations thereof with Electrically Mediated Therapeutic AgentDelivery (EMTAD).

In one aspect, the present disclosure provides an apparatus for thedelivery of a therapeutic agent to a predetermined site within a subjectcomprising an administrator for controlled administration of thetherapeutic agent to the subject comprising a reservoir or vessel forthe therapeutic agent, at least one orifice through which the agent isadministered, and a controlled source of energy sufficient to transfer apredetermined amount of the therapeutic agent at a predetermined ratefrom the reservoir or vessel through the orifice to the predeterminedsite within the subject. In addition, the apparatus comprises aplurality of penetrating electrodes arranged with a predeterminedspatial relationship relative to the orifice, and an electrical signalgenerator operatively connected to the electrodes. The terms reservoirand vessel are used interchangably throughout the specification to referto a container for the therapeutic agent.

In certain aspects of the present disclosure, EMTAD can be refered to asthe administration of a therapeutic agent to a biological tissue ofinterest and the earlier, concurrent or subsequent application ofelectrical signals to biological tissue for the purpose of enhancingmovement and/or uptake of the therapeutic agent in said tissue. Theprocess of EMTAD is comprised of two elements: 1) Therapeutic AgentAdministration (TAA), and 2) an Electrical Signal Application (ESA)sufficient to induce the desired EMTAD effect. In the presentdisclosure, therapeutic agent administration can be accomplished, forinstance, in a controllable fashion, termed Controlled Therapeutic AgentAdministration (CTAA). The term CTAA used herein refers to methods andapparatus that provide spatial and/or temporal control overadministration of a therapeutic agent relative to the induction of anEMTAD effect. Controllable administration techniques can utilizevariations on the conventional needle-syringe (e.g. automatic injectiondevice) and/or various needleless methodologies (e.g. jet injector,transdermal/transcutaneous patch, oral, gel, cream, or inhaledadministration). The term ESA used herein refers to the application ofelectrical signals to facilitate or enhance the delivery of therapeuticagents by improving movement and/or uptake of said agents within tissue,thus inducing an EMTAD effect. When used to facilitate or enhancedelivery of a therapeutic agent, ESA processes such as electroporation,iontophoresis, electroosmosis, electropermeabilization,electrostimulation, electromigration, and electroconvection allrepresent various modes of EMTAD.

Specific applications for apparatus and systems described hereininclude, but are not limited to, the delivery of vaccines, therapeuticproteins, and chemotherapeutic drugs. Traditionally with suchapplications, EMTAD is initiated by therapeutic agent injection using aconventional needle-syringe. After the agent has been administered, adevice suitable for ESA is applied to the subject at a designatedlocation. Finally, an appropriate ESA protocol is utilized to providethe desired facilitation or enhancement to therapeutic agent delivery.With traditional EMTAD, however, the desired spatial and temporalrelationship between agent administration and ESA may not be realized.

Spatial Parameters

In some embodiments of the systems, methods and apparatus describedherein, therapeutic agent administration is performed using aconventional needle syringe. The need to deliver certain agents withEMTAD brings an additional level of complexity to the issue of TAA. Asdepicted in FIG. 1, in any conventional needle-syringe injection, as theneedle 5 is inserted into the tissue, the depth 1 and the angle 2 ofinsertion relative to the surface of the tissue 3 can be difficult tocontrol. Additionally, the point of needle penetration 4 at the tissuesurface 3 may not be representative of the location of the orifice 6 andthe region of agent administration 7 within the target tissue. As anillustrative example a transcutaneous intramuscular injection may notcorrespond to the site of insertion on the skin since the two tissuescan often move in relation to one another.

While this conventional approach is generally adequate for the deliveryof many different therapeutics that do not require EMTAD, thesevariables lead to a distribution of the therapeutic agent followinginjection that is often inconsistent and/or indeterminate and can hampereffective EMTAD. In certain embodiments described herein, the mosteffective use of EMTAD utilizes a predefined relationship between thetherapeutic agent and ESA within the subject. As a result, in theabsence of spatial control over TAA in a target tissue, using aconventional needle syringe can result in reduced effectiveness of theEMTAD application, as compared to an apparatus, method or system thatprovides spatial and temporal control. One illustrative example of thisconcept is the use of electroporation to facilitate the delivery of atherapeutic agent. Electroporation is typically most effective inenhancing therapeutic agent delivery when TAA and ESA are co-localizedwithin the target region of tissue. In many cases, if the agent to bedelivered and the induced electroporation effect are not co-localizedwithin the target region of tissue, the delivery of said agent issuboptimal.

Another example of the need for adequate spatial control of TAA in EMTADis iontophoresis. This mode of EMTAD uses electrical fields to causemovement of charged molecules. In order to achieve the desired movementof the agent, the proper spatial relationship between the electrodes andthe therapeutic agent must be realized. If a negatively charged agentwere placed in close proximity to the location of a positive electrode,little or no movement of the agent through the tissue would be observed.In contrast, localization of the said negatively charged agent near thenegative electrode would result in significant movement of the agentthrough the tissue in the direction of the positive electrode.

As illustrated by the preceding examples, it is important to control theprecise location of TAA relative to the application of ESA to achievethe desired effect. As such, embodiments of the apparatus and methodsdescribed herein provide control of the precise location of TAA relativeto the application of ESA, and are useful to achieve reproducible,consistent, and well-characterized distribution of one or moretherapeutic agents.

Temporal Parameters

In the case of conventional needle-syringe injection TAA is that therate of injection may vary from one operator to another, thereby causinginconsistent agent distribution in the tissue. Additional temporalvariability is introduced when multiple device placements are requiredto complete the EMTAD process. For example, one application of EMTADcalls for the administration of plasmid DNA encoding for a therapeuticprotein, followed by generation of an electroporation-inducingelectrical field. Using the traditional method of EMTAD, the plasmid isinjected with a needle-syringe, followed by placement and activation ofthe electroporation device. By requiring two separate device placements(the initial needle syringe followed by the ESA device), this procedureis susceptible to inter-subject variability arising from inconsistenttemporal application of each device by the operator. Additionally, theuse of two separate device placements leads to an unavoidable timeinterval in between the clinician's placement and activation of eachdevice. This is compounded in the case where multiple application sitesare necessary to achieve adequate delivery of the agent to a specifiableregion within the target tissue.

These issues are especially critical for agents, such as nucleic acids,that can be degraded or inactivated in the extracellular environment.Therapeutic agent degradation can lead to a reduction in efficacy andconsistency in the application of the therapy. Also, the inter-subjectrate of therapeutic agent degradation is not constant, thus contributingto the overall therapeutic inconsistency of conventional needle-syringeinjection combined with ESA, and more specifically with electroporationtherapy.

Due to the inherent difficulty of spatial and temporal variability withconventional needle-syringe injection used in conjunction with ESA, theprecise location and timing of TAA relative to ESA is often unknown. Asa result, the effective administration and dosing of therapeutic agentswith EMTAD may be inconsistent and irreproducible. Though conventionalneedle-syringe injection is sometimes adequate for therapeutic agentadministration, reproducible and consistent agent delivery issignificantly enhanced by controlling the spatial and temporalrelationship between administration of the therapeutic agent andinduction of the desired EMTAD effect.

Thus, while the traditional EMTAD procedure may be adequate for certainapplications, temporal and spatial control is highly desirable forclinical applications that typically require a high degree ofconsistency and reproducibility. In contrast to the conventional EMTADapproach, embodiments of methods, systems and apparatus described hereinfacilitate CTAA and ESA to provide more advantageous methods andapparatus for the clinical application of EMTAD. The present disclosureutilizes various aspects of CTAA in conjunction with ESA to providereproducible, consistent, and efficacious therapeutic agent delivery.The present disclosure describes methods and apparatus to providespatial and temporal control over administration of a therapeutic agentrelative to the application of electrical signals, thereby improving themovement and/or uptake of said agent in the target tissue.

In some embodiments are provided methods and apparatus wherein thereexists a controllable spatial relationship for the administration of thetherapeutic agent relative to the application of electrical signals.Prior to treatment, the optimal location for TAA relative to ESA isdetermined. This spatial relationship between TAA and ESA is dictated bytreatment parameters, including the nature of the agent beingadministered and the properties of the target tissue to which the agentis administered. In an exemplary embodiment, electrical signals arepreferentially applied distal to the site of therapeutic agentadministration. In certain other embodiments, spatial relationship is toapply the EMTAD-inducing electrical signals proximal to the site ofagent administration. In certain cases, co-localization between TAA andESA is preferable. This is often the case when electroporation and/oriontophoresis are utilized for induction of the desired EMTAD effect.

In another aspect of the present disclosure, an apparatus describedherein provides a controllable temporal relationship for the sequenceand timing of TAA relative to ESA. Prior to treatment, the optimalsequence and timing for combination of TAA and ESA is determined. Aswith the spatial relationship, the desired temporal relationship betweenTAA and ESA is dictated by parameters such as the nature of the agentbeing administered and the properties of the target tissue to which theagent is administered. In certain applications, exposure to theelectrical fields associated with ESA may adversely affect thetherapeutic agent. In the practice of such applications, generation ofsuch electrical fields is followed by CTAA. However, the typicaltemporal relationship is CTAA followed by ESA.

The present disclosure provides improved methods and apparatus for thereproducible, consistent, and efficacious delivery of therapeuticagents, such as nucleic acid based constructs, pharmaceutical compounds,drugs, and proteins, with EMTAD. This objective is accomplished bycontrolling the spatial and temporal administration of a therapeuticagent relative to application of electrical signals. Exemplarytherapeutic agents for EMTAD include, but are not limited to, thedelivery of vaccines, therapeutic proteins, and chemotherapeutic drugs.In a certain embodiment, EMTAD is initiated by therapeutic agentinjection using a conventional needle-syringe. After the agent has beenadministered, a device suitable for ESA is applied to the subject at adesignated location. An appropriate ESA protocol is utilized to providethe desired facilitation or enhancement to therapeutic agent delivery.An exemplary ESA method that has proven to be effective in virtually allcell types is electroporation. Other exemplary methods of electricallymediated delivery include, but not limited to, iontophoresis,electroosmosis, electropermeabilization, electrostimulation,electromigration, and electroconvection. These terms are used forillustrative purposes only and should not be construed as limitations inthe present disclosure.

The technique of electroporation utilizes the application of electricfields to induce a transient increase in cell membrane permeability andto move charged particles. By permeabilizing the cell membranes withinthe target tissue, electroporation dramatically improves theintracellular uptake of exogenous substances that have been administeredto the target tissue. The increase in cell membrane permeability andmolecular movement due to electroporation offers a method for overcomingthe cell membrane as a barrier to therapeutic agent delivery. Theapplication of electroporation as a technique for inducing EMTAD isadvantageous in that the physical nature of the technique allowselectroporation to be applied in virtually all tissue types.Accordingly, various aspects and embodiments of the present disclosurediscuss, but are not limited to, electroporation as a technique forinducing EMTAD.

Therapeutic Agents

The term “therapeutic agent” is used herein in its broadest sense toinclude any agent capable of providing a desired or beneficial effect onliving tissue. Thus, the term includes both prophylactic and therapeuticagents, as well as any other category of agent having such desiredeffects. Clearly, the scope of the present disclosure is sufficientlybroad to include the controlled delivery of any agent, howevercategorized. Therapeutic agents include, but are not limited topharmaceutical drugs and vaccines, and nucleic acid sequences (such assupercoiled, relaxed, and linear plasmid DNA, RNA, antisense constructs,artificial chromosomes, or any other nucleic acid-based therapeutic),and any formulations thereof. Such agent formulations include, but arenot limited to, cationic lipids, cationic and/or nonionic polymers,liposomes, saline, nuclease inhibitors, anesthetics, poloxamers,preservatives, sodium phosphate solutions, or other compounds that canimprove the administration, stability, and/or effect of the therapeuticagent. Additional formulations include agents and additives conferringthe ability to control viscosity and electrical impedance of theadministered agent.

In the case of nucleic acids, an example of a therapeutic agent would beplasmid DNA dissolved in a phosphate buffered sodium chloride solutionwith a competitive nuclease inhibitor such as aurintricarboxylic acid(ATA) added to the agent. In some embodiments using nucleic acid-basedtherapeutics, it may also be advantageous to incorporate a signalingpeptide onto the construct. Potentially useful peptides include, but arenot limited to, nuclear localization signals, endosomal lyric peptides,and transcriptional control elements. These signals can enable improveddelivery and/or processing of the therapeutic agents delivered to thecells via EMTAD. This signaling can be accomplished through the use ofmethods as described in U.S. Pat. No. 6,165,720 (the entire disclosureof which is incorporated by reference herein). While these techniquescan be utilized with other delivery systems, the ability of EMTAD toincrease the delivery of nucleic acid constructs to target tissues makesit particularly well suited for use with such signals.

Target Tissues

Target tissues well suited for EMTAD by use of methods, apparatus andsystems described herein include both healthy and diseased cells locatedin, for instance, the epidermis, dermis, hypodermis, connective, andmuscle tissue. The technique can also be utilized for application inhealthy or diseased organs that must be accessed via minimally invasiveor other surgical methods. Such target tissues include the liver, lungs,heart, blood vessels, lymphatic, brain, kidneys, pancreas, stomach,intestines, colon, bladder, and reproductive organs. In someembodiments, a desired therapeutic effect can be derived by use of amethod, or apparatus described herein to deliver an amount of agent tocell types normally located within the target tissues as well as othercell types abnormally found within said tissues (e.g. chemotherapeutictreatment of tumors).

As discussed previously, and depicted in FIG. 1, traditional EMTADsuffers from a lack of precision and reproducibility in the spatial andtemporal relationship between the administration of the therapeuticagent and the electrical signal. In contrast to the traditional EMTADapproach, the present disclosure describes methods and apparatus forcombined CTAA and ESA to provide a more advantageous clinicalapplication of EMTAD. The present disclosure utilizes various aspects ofCTAA in conjunction with ESA to provide reproducible, consistent, andefficacious therapeutic agent delivery. The methods and apparatusprovided herein provide spatial and temporal control over administrationof a therapeutic agent relative to the application of electricalsignals, thereby improving the movement and/or uptake of said agent inthe target tissue.

Methods

In one aspect, the present disclosure described herein provides systemsand apparatus for use in methods for controlled administration of atherapeutic agent followed by ESA. In another aspect, the presentdisclosure described herein provides systems and apparatus for use inmethods for controlled administration of a therapeutic agent preceded byESA. In a further aspect, the present disclosure described hereinprovides systems and apparatus for use in methods for controlledadministration of a therapeutic agent paccompanied by ESA. These methodsinclude, but are not limited in scope or sequential relationship to, thedetermination of treatment parameters, subject preparation procedures,CTAA, ESA, and additional measures.

Determination of Treatment Parameters

In some embodiments, treatment parameters are based on the desiredamounts and/or duration of dosing of the therapeutic agent. Therapeuticagent dosing can depend, for instance, on the particular indication ortreatment application (such as the type and location of the targettissue), as well as various subject parameters (such as age and bodymass). Dosing of the therapeutic agent can be controlled by parameterspertaining to administration of the therapeutic agent and ESA. Exemplarycontrollable parameters pertaining to CTAA include, but are not limitedto, agent volume, agent viscosity, and injection rate. Exemplarycontrollable parameters pertaining to ESA include, but are not limitedto, the characteristics of the electrical signals, the tissue volumeexposed to the electrical signals, and the electrode array format. Therelative timing and location of CTAA and ESA are parameters providingfurther control over therapeutic agent dosing.

Patient/Subject Preparation

In embodiments described herein, methods described herein may include apatient/subject preparation step. The subject preparation may include,but is not limited to, antiseptic cleansing and anestheticadministration, including local or regional, nerve block, spinal block,epidural block, or general anesthesia. In an exemplary case ofintramuscular (IM) ESA, protocols to minimize the effects of electricalstimulation of the muscle may be included in a method described herein,for instance, including thermal control (e.g. cooling the muscle),administration of anesthetics, and/or alternative stimulation patternssufficient for mitigation of discomfort. It is to be understood that theselected subject preparation techniques do not adversely affecttherapeutic efficacy, if acceptable alternatives exist. For example, ithas been shown that in some cases, the intramuscular administration ofamide based anesthetics can have an undesirable effect on intramusculardelivery plasmid DNA-based therapies, putatively due to the mildmyotoxicity of these agents, which can inhibit the muscle cells abilityto express the protein encoded by the administered DNA sequence.

CTAA and ESA

In some embodiments described herein, is a method wherein CTAA and ESAare combined, enabling consistent and reproducible therapeutic agentdelivery. In some cases, are provided apparatus suitable for CTAA,including for instance apparatus comprising at least one of automaticinjection devices and jet injectors.

The present disclosure provides methods and apparatus enabling thetranscutaneous deployment of a plurality of elongate electrodes to atarget depth in a safe and consistent manner with respect to a targetsite of agent distribution in recipients with heterogeneous skinthickness and composition in order to support the application ofelectrical fields in tissue to enhance the intramuscular, intradermal,and/or subcutaneous administration of therapeutic or prophylactic agentssuch as nucleic acids, pharmaceuticals, antibodies, peptides, proteins,or combinations thereof.

Systems and methods according to present principles enable theconsistent transcutaneous deployment of a plurality of elongate, tissuepenetrating electrodes to a pre-determined target tissue site in orderto propagate electrical fields in the skin, subcutaneous tissue and/orskeletal muscle. The present disclosure provided herein is designed toenable a user with minimal training to consistently deploy theelectrodes to a target depth while maintaining the proper spatialrelationship among the plurality of electrodes, even when the procedureis applied at sites with varying skin characteristics. Such variationcan be due either to variation in skin characteristics at differentsites within an individual or among heterogeneous recipient populations.In other words, systems and methods according to present principlesshould allow a consistent profile irrespective of the administrator orthe recipient. In certain embodiments, the deployment of the electrodesis accompanied by the insertion of one or more injection needles whichare configured for the administration of therapeutic agents to thetarget region of tissue and arranged in a pre-determined spatialrelationship with the electrodes to be used for ESA. In an exemplaryembodiment, the electrodes are arranged such that any electrical signalsfrom said electrodes are preferentially applied distal to the site oftherapeutic agent administration by the insertion of one or moreinjection needles. In another embodiment, the electrodes are arrangedsuch that any electrical signals are preferentially applied proximal tothe site of therapeutic agent administration by the insertion of one ormore injection needles.

Aspects of the present disclosure can be used singly or in combinationto support the transcutaneous insertion of electrodes for the in vivoapplication of electrical fields to enhance the intramuscular,intradermal, and/or subcutaneous administration of nucleic acids, smallmolecule drugs, antibodies, peptides, proteins, and combinationsthereof. In some embodiments, the electrode deployment and subsequentelectrical field propagation are performed in coordinated fashion withthe distribution of the agent of interest to the target tissue site. Inan exemplary embodiment, the administration of the agent and theapplication of one or more electrical field are performed in acontrolled and monitored fashion such that the probability of achievingspatial and temporal co-localization of the distribution of the agentwith the site of electric field application is maximized.

In general terms, the present disclosure provides methods and apparatusfor the transcutaneous deployment of electrodes to a predetermined sitewithin the skin, subcutaneous tissue, and/or skeletal muscle of arecipient in conjunction with the administration of an agent of interestand the local application of electrical fields to improve the delivery,uptake, and/or biological effect of the agent. In some embodiments, thepresent disclosure has been implemented such that set up and usage ofthe device can be performed effectively and reliably by users withminimal training. In another embodiment, the present disclosure alsocomprises the implementation of numerous interlocks, sensors, andfeedback loops to reduce the frequency and/or potential impact ofpotential user errors committed during the set up and use of the device.Referring to FIG. 2, one embodiment of an apparatus described hereincomprises a “cartridge assembly” 100 detachably interfaced to an“applicator” 400 which is configured to connect to a controller 700which acts as source of electrical energy for electrode activation andsubsequent electrical field generation, as well as diagnostics and othercontrol routines. The controller 700 further provides a user interface,tray, holster for the applicator 400, and various other features aredescribed. As seen in FIG. 2, a reservoir or vessel 101 of suitableuniform size and general shape can inserted in the cartridge assembly100 in a method of use.

Details of a cartridge assembly 100 present in some embodiments of anapparatus described herein, are described for instance, in FIGS. 3A-12,along with corresponding cooperating portions of the applicator 400, inFIGS. FIGS. 13A-18C, followed by, where relevant, portions of thecontroller 700, in FIGS. 19-20D. Remaining portions of the applicator400 are described next, followed by remaining portions of the controller700.

Referring in addition to FIGS. 3A-4, in some embodiments describedherein, the cartridge assembly 100 can comprise a support structureconfigured to interface with the applicator 400 and accommodating two ormore elongate electrodes 122 mounted on the structure to form an array.To avoid unwanted propagation of electrical currents within the device,the design and materials of the electrode mounting structure should bespecified such that there is an adequate dielectric barrier betweenelectrodes of opposite polarity within the device. The distal region 137of the elongate electrodes are engaged with the mounting structure usingstandard mechanical features and/or bonding agents appropriate for thematerial composition of the electrode mount structure and theelectrodes.

In an exemplary embodiment, the cartridge outer housing structure 102 isconfigured to interface with a fluid reservoir or vessel 101 containingthe agent of interest where the reservoir or vessel 101 and cartridgehousing structure 102 are configured to operatively connect to at leastone injection orifice (needle 105) through which the agent isadministered into the target tissue. In some embodiments, thisconfiguration facilitates the co-localization of the distribution of theagent of interest with the site of electrical field application. Inanother embodiment, this configuration facilitates the implementation ofa pre-determined spatial relationship between the apparatus for ESA andCTAA. In yet another exemplary embodiment, a syringe 101 is insertedinto a cartridge 100, wherein upon loading of the cartridge into anapplicator 400, the syringe 101 moves forward to mate with the needlehub 152 and to connect the cartridge to the needle.

Certain embodiments of the present disclosure can include the use ofsyringes, vials, ampoules, cartridges or equivalent structures forstoring one or more therapeutic agents. In some embodiments, thereservoir or vessel can comprise at least one of glass and plastic, withthe material selected for compatibility with the agent of interest.Coatings may be applied to the reservoir or vessel used to providedesirable lubricious or protective properties. As disclosed above, theelectrodes 122 may be hollow and in some cases configured with injectionorifices that can be operatively connected to the fluid vessels.Alternatively, the injection orifice can comprise one or more hypodermicneedles and/or needle free injection ports positioned relative to theelectrodes. Selection of the type and size of injection orifice candependent on the desired route of administration, tissue distribution,and physical characteristics of the agent of interest. In a certainembodiment, the cartridge structure is designed to ensure apre-determined spatial relationship between the injection orifice andelectrodes in their deployed state such that the distribution of theagent of interest occurs substantially in the tissue bounded by theconductive regions of the plurality of electrodes. To minimize the needfor handling of sharps by the user, in a certain embodiment, a cartridge100 designed for use with hypodermic needles is configured to allow thehypodermic needle to be mated to the cartridge at the time ofmanufacture rather than the more common convention of mating the needleto the syringe at the time of use. In certain embodiments, an aspect ofthe present disclosure can incorporate features in the cartridge and/orthe needle to ensure retention of the needle during manufacture,distribution, handling, and use as well as features to ensure thatproper mating of the reservoir or vessel to the needle prior to the use.In some embodiments, such features can minimize the risks of leakage ofthe agent from the reservoir or the reservoir orifice interface due tobreakage or improper mating.

In certain embodiments, the cartridge can include a tissue contactinterface located at the distal end of the subassembly. In certainembodiments, the tissue contact interface comprises a substantiallyplanar structure oriented perpendicular to the elongate orientation ofthe electrodes and having one or more apertures configured to allowpassage of the electrodes through the tissue contact interface. Forembodiments incorporating an integrated reservoir or vessel andinjection orifice, the interface also has apertures to accommodateinjection orifice or needle free injection. To minimize the risk ofcontamination of the electrodes and injection needle as well as theoccurrence of unintended sharps exposure to the user or recipient, in acertain embodiment, the apertures accommodating passage of theelectrodes and injection needle are of a size suitable to preventaccidental contact with the electrodes and injection needle. Mostcommonly, the tissue contact interface is comprised of one or moreplastics suitable for at least short term tissue contact.

To avoid potential cross contamination of biological material betweenrecipients, the cartridge assembly 100 can be configured for single use.In some cases, the cartridge includes one or more mechanical,electrical, and/or identification elements which restrict use of thecartridge to a single administration. Examples of mechanical elements ofthis nature include for instance, but are not restricted to, lockoutsand/or detents which secure the electrode mount structure and/or thestick shield (see below) in the deployed state after use. Examples ofelectrical elements include for instance, fuses or links configured inseries with one or more electrodes which are deactivated by the sourceof electrical energy at the conclusion of the first use of thecartridge. Examples of identification elements include, for instance,serialized radio frequency identification devices, bar codes, or quickresponse codes configured to be read by the applicator and/or the sourceof electrical energy. The identification information for a specificcartridge can then be used to prevent accidental or intentional re-useof that cartridge by the applicator and/or the source of energy. In anembodiment, one or more redundant features are incorporated to minimizethe potential for re-use of the cartridges.

In an embodiment of an apparatus described herein, as shown in FIG. 2,the applicator 400 comprises a support structure configured to interfacewith the cartridge assembly 100, a user interface 410-418 (FIG. 13B),electrically conductive electrical connections configured to provideoperative connection between the conductive contact region located onthe distal region of the elongate electrodes and the source ofelectrical energy when the electrodes are deployed into the targettissue of the recipient. In some cases, the user interface comprises ahandle, one or more display features designed to convey information tothe user, and one or more features capable of accepting user input. Incertain embodiments, the display features are configured to convey theoperating status of the device during its set up and use as well asrelevant warning/error messages. Such displays can comprise mechanicalfeatures, lights, alphanumeric displays, and/or electronic displayscreens. In some cases, the features capable of accepting user input areconfigured to allow the user, at the appropriate stage of the procedure,to de-activate safety features within the device preventing accidentaldischarge, make selections regarding particular parameters of theprocedure (e.g., the intended depth of injection), and to initiateprocedure administration and can include buttons, triggers, mechanicalslides, and/or levers.

In certain embodiments, the applicator 400 also includes actuationmechanisms which interface with the cartridge assembly and which areconfigured for transcutaneous deployment of the electrodes, positioningof the injection orifice relative to the target tissues, discharge ofthe agent of interest from the reservoir or vessel through the orificeand into the target tissue site, and/or conveying electrical signalsfrom an electric field generator such as a controller 700 to thecartridge 100. The applicator 400 can be configured such that the energyto actuate the mechanisms is supplied by the user, or more preferably,the apparatus may incorporate one or more inanimate sources of energyoperatively connected to the actuation mechanisms within the applicator.Such inanimate sources of energy include for instance, electromechanicaldevices (solenoids, motors, lead screws), mechanical components (springsand related devices), and compressed gases.

An exemplary implementation of a cartridge assembly 100 is as describedin FIG. 3A, a cartridge assembly 100 includes a reservoir or vesselloading port 140 and a reservoir or vessel containment volume 142 toreceive and contain a reservoir or vessel 101 of a medicament. Acartridge assembly 100 is required because, for a device in which anelectrical field is to be generated and used as part of a therapy, anelectric field generator such as a controller 700 is required toelectrically interface with the device containing the electrodesconfigured to contact the target tissue. As the controller can beconfigured for multiple uses, and the reservoir or vessel 101 can beintended for single use, the cartridge assembly 100 can be present tohold the electrodes 122 and, the reservoir or vessel 101, to interfacewith the re-usable device, and for the cartridge assembly 100 to beconfigured for single use. Thus, the applicator 400 can be a reusablecomponent and the cartridge assembly 100 can be configured for singleuse. The cartridge assembly 100 can also be rendered in a condition toprevent subsequent use if errors or tampering occur in the insertion ofa reservoir or vessel 101, or if defects are present.

The term reservoir or vessel 101 can refer to a syringe, vial, or anyother device which can contain a medicament or therapeutic agent andwhich can interface with a device having an orifice, such as a needle,shown in FIG. 4 as a needle 105 having a needle hub 152. The reservoir101, for a given type of cartridge assembly 100, generally has a commonshape and size. Various components within the cartridge assembly 100allow for a leeway in exact sizing and/or manufacturing tolerances, butgenerally a common shape and size are required to reduce the risk thatdrugs not labeled for use with cartridge 100 are erroneously deliveredwith the device. If an appropriately sized reservoir 101 is not providedby the user, one or more interlocks within the cartridge assembly 100may be unable to deactivate, and the system may be rendered unusableuntil a proper-sized reservoir 101 is inserted.

As seen in FIG. 3B, the reservoir 101 generally can be equipped with aplunger and a port 156 for drug egress. A removable cap 158 can also beprovided to maintain the sterility and integrity of the agent until suchtime as the reservoir is to be inserted and used. The port for drugegress can be proximal to the needle hub 152 in use, and the plunger canbe opposite this port for drug egress. As an alternative to an open portfor drug egress, in some embodiments, the reservoir or vessel can beconfigured with a septum component which covers and seals the end of thecontainer opposite the plunger. The septum can be made of elastomericcompounds such as silicone or butyl rubber, with the specificformulation and coating of the material selected for stability andcompatibility with the agent contained within the reservoir or vessel.The septum component is typically held in place by a crimp seal or otherfastening mechanism. This septum seal configuration obviates the needfor a removable cap, but requires that needle 105 be equipped with asuitable piercing member such as a needle, spike, or other features toaccess the fluid contained in the reservoir or vessel. Specificimplementations for this configuration include dual sided needleconfigurations and spike vial adapters.

The cartridge assembly 100 is not only configured for receiving thereservoir or vessel 101 but also for being received by an applicator 400in an applicator cartridge assembly receiving port 401 (FIG. 2). Thus,the cartridge assembly 100 includes a device allowing the applicator 400to pull and retain the same within an interior volume, at leastpartially. In certain embodiments, the device is one or more racks onthe surface(s) of the cartridge assembly 100 that engage a correspondingmotorized pinion assembly in the applicator 400. In otherimplementations, the applicator 400 can interface with the cartridgeassembly 100 without the need to pull the same into an interior volume.In yet other implementations, other techniques may be employed to causethe cartridge assembly 100 to engage the applicator 400, e.g., motorizedtracks or brackets and the like onto which the cartridge assembly 100can interface.

The applicator 400 is further provided with interface elements allowingthe same to control certain actions within the cartridge assembly 100.In particular, the applicator 400 can be configured to control needleinsertion, medicament delivery, electrode insertion, and electrodeactivation using various subsystems. In some cases these steps arelinked, so that a single action of applicator 400 initiates multiple ofthese steps. In some implementations, all of these steps but themedicament delivery and electrode activation are caused by a singleaction, as described in the exemplary implementation below.

Upon appropriate activation, such as the use of electrical or opticalsignals conveyed to mechanical, electrical, or optical elements of thecartridge assembly 100, the applicator 400 can be enabled to testsubsystems within the cartridge assembly 100, ensuring that the same areoperating properly and are properly configured for medicament deliverywith electric field application. For example, such subsystems includethat the applicator 400 can test to ensure that the cartridge assembly100 has not been previously used, that the reservoir or vessel has beenproperly placed within the cartridge assembly, that appropriate forceapplied against the body of a subject as applied through an alignmentguide/splay shield 108, a test that a depth has been affirmativelyselected by the user, and that an exterior cartridge cap 110 has beenremoved. Moreover, the applicator 400 can be configured to monitor thestatus of the cartridge functions during execution of the procedure. Forexample, such subsystems include that the applicator 400 can test toensure that that electrodes 122 are properly deployed within a subjectprior to commencing with administration of the medicament, that theplunger in the reservoir or vessel has been appropriately actuated priorto application of the electrical fields, that the user has maintainedappropriate force applied against the body of the subject during theadministration procedure, and so on.

In addition to the subsystems that are operated by the applicator 400,the cartridge assembly 100 can incorporate appropriate subsystems,including those that interact with the applicator 400 and those that donot so interact, so as to accomplish the goals of the medicamentdelivery and electric field application therapy. These include asubsystem for causing needle and electrode insertion, a subsystem forprotecting users from sharps following therapy administration, asubsystem for providing different depths of needle/electrodes insertion,a subsystem for ensuring that adequate force has been applied againstthe tissue of the recipient prior to allowing initiation of theprocedure and subsequently during application of the administrationprocedure and so on. While often described in the context of deployableneedles and electrodes, it is noted here that such are not strictlyrequired, and that systems with non-deployable or fixed needles andelectrodes also benefits from systems and methods according to presentprinciples, including the subsystems described.

In one exemplary implementation, as shown in FIG. 4, the cartridgeassembly 100 includes an outer cartridge 102, in some cases termed ahousing. The outer cartridge 102 is terminated at a distal end by anouter cartridge cap 106. The outer cartridge 102 includes an innercartridge containment volume 150, for receiving an inner cartridge 103,which is received and moves in a slidable manner in relationship to theouter cartridge 102. The inner cartridge 103 includes a reservoir orvessel containment volume 142 in which the reservoir or vessel 101 maybe situated. The inner cartridge 103 engages with an inner cartridge cap104 at a distal end. The inner cartridge cap 104 has a number offunctions, including to lock electrodes 122 in place (the innercartridge 103 itself has seams that the electrodes 122 are placed into)and to provide a bearing surface for a stick shield 134. The innercartridge cap 104 locks onto the inner cartridge 103.

A cartridge breech 112 is received in a portion of the reservoir orvessel containment volume 142 in the inner cartridge 103, in a portionopposite that of the inner cartridge cap 104. A vessel detection cap 118engages the cartridge breech 112 through a vessel detection spring 116.A cartridge lock ring 114 locks the system in place, including thecartridge breech 112 to the inner cartridge 103. The vessel detectionspring 116 also serves to push the reservoir 101 into engagement withthe needle hub 152, and also serves to accommodate tolerances in thesize of reservoir 101.

A vessel interlock 120 provides a mechanical interlock to preventinadvertent or unwanted actuation of cartridge functions. In particular,the vessel interlock 120, also termed a first reservoir insertiontrigger, is placed below the inner cartridge 103 and has fingers thatextend through slots or holes defined in the inner cartridge 103 (seeFIG. 5B). The fingers prevent the cartridge breech 112 from slidablymoving relative to the inner cartridge 103, and in particular frommoving within the inner cartridge 103 towards the inner cartridge cap104 before a reservoir has been inserted into a vessel containmentvolume 142.

When a reservoir or vessel 101 is properly inserted in the reservoir orvessel containment volume 142, the reservoir or vessel interlock 120 ispushed down and the fingers are pushed down, no longer extending intothe vessel containment volume 142. This pushing down or depression ofthe vessel interlock 120 may also be configured to provide an audible,tactile, or haptic “click” that can inform the user of proper insertion.Once depressed, the cartridge breech 112, no longer blocked by thefingers of reservoir or vessel interlock 120, is then permitted to move,and in particular is permitted to move in the direction towards theinner cartridge cap 104.

The cartridge breech 112 is caused to move such by the action of thespring cap/cartridge interface 470 when the cartridge assembly 100 isinserted in the applicator 400 in a fashion described below. When thecartridge breech 112 moves far enough forward, it locks in place,securing the reservoir or vessel 101 in the reservoir or vesselcontainment volume 142 and ensuring that it is properly positionedrelative to the needle hub 152 to ensure an intact fluid pathway fromthe reservoir 101 to the orifice of needle 105.

For embodiments of the device where the injection needle is incorporatedinto the cartridge 100, the use of standard “off the shelf” single usehypodermic injection needles may be employed within the device. However,the operational and reliability characteristics of the device may beimproved through the incorporation of customized design elements thatare not present in hypodermic needles intended for conventionalparenteral administration procedures. Specific aspects of the needle hub152 can include the material from which it is comprised, the inclusionof retention features to prevent the needle hub 152 from becomingdislodged from inner cartridge 103 during distribution and use, and theorientation of any bevel features in the needle relative to the hub.

Conventional single use disposable injection needles are commonlycomprised of injection molded polypropylene thermoplastic. However, formany applications, the impact strength, tensile strength, and flexuralstrength of polypropylene may not be adequate to ensure integrity of thehub when subjected to the forces characteristic of needle deployment andinjection with this device. Specific failures of concern include failurein the hub wall due to impact or injection forces as well as failure ofthe hub needle joint due to same. While adjustments in the design of thehub, including its geometry and wall thickness may be utilized toaddress prevent these failures, it is not always feasible to modify thedesign sufficiently to prevent hub failure while ensuring that the hubretains the dimensional properties required for proper mating to aconical male luer slip connectors as described in the relevant standardpublished by the International Standards Organization (ISO) ISO80369-7:2016 Small-bore connectors for liquids and gases in healthcareapplications—Part 7: Connectors for intravascular or hypodermicapplication. Specifically, given the forces that the syringe needle andhub are subjected to during deployment, in certain embodiments, amaterial with improved impact strength, tensile strength, and flexuralstrength is used. One example is the use of injection moldedpolycarbonate plastics (such as ZELUX® GS, Makrolon, or Lexan) orcopolyesters (such as Eastman Tritan™ Copolyester MX731, MX711, and MX730). When assessed according to ISO 180:2000 Plastics—Determination ofIzod impact strength, a notched impact strength of at least 70 kJ/m2 isconsidered suitable for this application. When assessed according to theISO 527-1:2012 Plastics—Determination of tensile properties—Part 1:General principles, a tensile strength of at least 30 MPa is consideredsuitable for this application. When assessed according to ISO 178:2010Plastics—Determination of flexural properties, a flexural strength of atleast 50 MPa is considered suitable for this application. In someembodiments, the specific resin selected exhibits compatibility with theintended method of sterilization (e.g., gamma radiation) withoutexhibiting detrimental changes in its physical properties that couldcompromise its function.

For embodiments where a custom injection needle is utilized, one or moremechanical features are included which are not ordinarily present onconventional syringe hubs that enable the device to be inserted intoinner cartridge 103. Such features can include tabs, snaps, or ridgeswith corresponding mechanical features located on inner cartridge 103.In some cases, the features are implemented such that the hub mates withthe inner cartridge 103 in a consistent orientation. Combined with aneedle manufacturing process that is capable of consistently orientingthe bevel or other needle orifice feature, this insures that biases ininjection location or medicament distribution due to the location anddesign of the orifice can be accounted for in the design of the device.For example, needles with asymmetrical penetrating tip features (e.g., abevel cut) can exhibit a directional bias during deployment into tissuedue to interaction between the tissue and the asymmetrical penetrationfeature on the needle. If the electrodes have a symmetrical penetratingtip feature (e.g., a trocar tip) then the electrodes would not exhibit acorresponding bias in their deployment characteristics. Therefore,mounting feature for needle hub 152 on inner cartridge 103 can includean offset in the position of the injection orifice on needle 105relative the electrodes 122 prior to deployment to account for theexpected deployment characteristics of the asymmetrical bevel of theneedle. The precise dimension of the offset can depend on the nature ofthe target tissue and the expected range of penetration depths, but incertain embodiments the needle is offset by 0.5-1 mm for each 10 mm ofpenetration depth. When using electrodes and injection needles withdiffering tip profiles or where the tip profiles must be consistentlyoriented with one another, such features are advantageous for insuringco-localization of the medicament distribution with the application ofthe electrical fields.

The incorporation of a syringe detection cap 118 mounted to a syringedetection spring 116 ensures that the cartridge assembly 100 can acceptand properly position the syringe 101 relative to needle hub 152 acrossthe range of manufacturing tolerances expected for syringe 101. Theapplicator 400 causes the cartridge breech 112 to move forward duringthe loading procedure when the spring cap/cartridge interface 470 withinthe applicator 400 moves distally, relative to the cartridge assembly100. This action occurs when the cartridge assembly 100 is loaded intothe applicator 400 and the cartridge assembly 100 is pulled into theapplicator 400, e.g., by the action of a loading mechanism, e.g., arack-and-pinion mechanism described below.

The movement of the cartridge breech 112 can act as a second interlock.In particular, in one implementation, as seen in FIGS. 5C-5D, a line ofsight is visible and detectable, by an appropriately configured sensor,within the cartridge assembly receiving volume 403, through a set ofreservoir or vessel locking holes 144′ (FIG. 5D). This line of sight isvisible when the cartridge assembly 100 is loaded into the applicator400. The visible light of sight, or occlusion of the same, can act aspart of a second interlock that must be deactivated for the controller700 to allow activation and triggering of the device, including needleand electrode insertion, medicament delivery, and electrode activation.

For example, in one implementation, the reservoir or vessel lockingholes 144′ (FIG. 5D) must be occluded for the device to operate. If avisible line of sight is present, e.g., as detected by an IR or visiblelight emitter and detector paired within the cartridge assemblyreceiving volume 403 of the applicator, the device may be renderedinoperable and generate and display an error message on the applicatordisplay 404 and/or controller 700, including the controller display 712,to notify the user of the state of the device as well as the recommendedsteps to be performed to address the error.

Thus, in this implementation, one error state can be that no reservoir101 was loaded into the cartridge 100 or that the syringe was notproperly seated into the inner cartridge 103. In this case, the vesselinterlock 120 cannot be depressed as there is no reservoir 101 toperform this action. In this case, the cartridge breech 112 cannot bemoved forward, in the distal direction, towards the inner cartridge cap104. The construction of these components can be such that an openbreech state results in an open line of sight 146 through firstreservoir locking holes 144′ (FIG. 5D). An ancillary check is that thecartridge breech 112 cannot be closed, and this can manifest itself asan inability of the cartridge to move the required distance backward ordistally into the cartridge assembly receiving volume 403. As theseconditions are defined by the system to be an error state, the same canbe identified and used in the generation of an error message, e.g., withan appropriate message to the user on a user interface on the applicatordisplay 404 and/or controller 700, including the controller display 712.A similar error state may occur if the reservoir 101 is improperlyloaded, or if the vessel interlock 120 is damaged. Generally in thiscase, an appropriate error message may be accompanied by instructions tothe user to remove the cartridge, reinstall a new reservoir, and attemptto reintroduce the cartridge assembly 100 into the applicator 400.

Another error state may be that the cartridge breech 112 is movedforward manually by the user without a reservoir 101 present, suchoccurring by the user manually pushing the vessel interlock 120 out ofthe vessel containment volume 142. This situation can also be defined asan error state, and the same can be detected because another (second)set of reservoir locking holes 144 (FIG. 5C) are placed on a portion ofthe outer cartridge 102. If no reservoir is in place, but the cartridgebreech 112 is moved forward by the action of the vessel interlock 120being depressed, then the reservoir locking holes 144′ (FIG. 5D) alignwith the reservoir locking holes 144 (FIG. 5C), again creating an openline of sight 146 and a subsequent error state. This error state mayalso occur if the reservoir or vessel interlock 120 is damaged and itsfingers are no longer within the vessel containment volume 142. In acertain embodiment, this error state need not be not remediable byattempting to reinstall a reservoir, as a reservoir may not fit in thevessel containment volume 142 with the cartridge breech 112 locked. In acertain embodiemnt, a new cartridge assembly 100 is required.

In contrast, if an appropriately sized reservoir or vessel 101 ispositioned properly in place, then the vessel detection cap 118 ispushed back against the vessel detection spring 116, and the movement ofthe vessel detection cap 118 occludes the reservoir locking holes 144(FIG. 5C) and the reservoir locking holes 144′ (FIG. 5D). In this casethere is no error state, allowing the device to operate. The occlusion,and detection of the occlusion, occurs within the body of the applicator400, after the cartridge assembly 100 is inserted, and thus isinsusceptible to user attempts to defeat this interlock, whetherintentional, accidental, or caused by a defect. It is noted that this“no error” state still occurs even if the user intentionally orinadvertently closes the cartridge breech 112 themselves during handlingof the cartridge 100.

Depending on which error state occurs, the cartridge assembly 100 canremain usable or not. If the cartridge breech 112 has been locked intoplace, the cartridge assembly 100 is rendered unusable. If, however, thecartridge breech 112 has not been locked into place, then the cartridgeassembly 100 can be removed from the applicator 400 and a new reservoir101 inserted.

While the above-noted set of two interlocks (one mechanical using vesselinterlock 120 and one using a light emitter and collector and reservoiror vessel lockout holes 144 and 144′) have been found particularlyuseful in some implementations, it is to be understood that other typesof interlocks can also be employed (FIGS. 5C-5D). For example, insteadof having an error state occur when the reservoir locking holes 144 arenot occluded, the error state may be configured to occur (via a changein reservoir locking hole location and program logic) when the reservoirlocking holes 144 are occluded (and the clear line of sight 146 thencorresponding to the non-error state). The vessel interlock 120 canincorporate additional mechanical flag features that are recessed in thecartridge when the interlock is active, but become visible to anappropriately configured sensor when the syringe 101 has been properlyinserted and the vessel interlock 120 is depressed into its releasedposition. In other variations, other ways may be employed to determineif a line of sight is present, e.g., optical, acoustic, electrical, orthe like, so long as a suitable emitter and collector can be positionedwithin the applicator 400. Other ways may also be employed to determineif the reservoir or vessel 101 is properly loaded, e.g., mechanicaltechniques, as it is to be understood by one of ordinary skill in theart given this teaching. Depending on implementation, if an error stateis detected, the applicator 400 may be prevented from operating eitherwith the cartridge assembly 100 in place, or the applicator 400 may beprevented from even accepting the cartridge assembly 100 in the firstplace. For example, the cartridge can be designed such that the vesselinterlock 120 includes mechanical tab or locking features which extendfrom one or more of the cartridge surfaces until an appropriate vessel,such as syringe 101 is properly inserted into the cartridge 100, thuspreventing inappropriate vessels from being used and improperpositioning of proper vessels. The mechanical tabs are designed tointeract with a corresponding detent feature located in the applicator400 such that loading of the cartridge 100 into the applicator 400 isphysically blocked unless the vessel interlock 120 is released—i.e.unless the tab is deflected or moved aside by a properly loaded vessel.This mechanical interaction would provide feedback to the user or thesystem that an error condition must be resolved before proceeding withthe loading of the cartridge 100 into applicator 400. In othervariations, more or less than two interlocks may be provided, althoughthe same may be correspondingly associated with a different safetyprofile.

In certain implementations, other features can also be employed in theabove determinations, or to enhance the above determinations. Forexample, where a motor is employed to pull the cartridge assembly 100into the applicator 400, sensors may be employed as described below todetect the spatial position of the cartridge assembly 100 during theinsertion process. Put another way, the applicator 400 may detect wherethe cartridge assembly 100 is within the cartridge assembly receivingvolume 403. In some cases, such may allow determination of additionalerror states either directly, or by prompting the activation ofadditional sensors to assess the state of the device. For example, in aused cartridge, the cartridge breech 112 is locked into position. If theused cartridge assembly 100 is attempted to be re-used, the opticaldetector detects the cartridge assembly 100 at a different point than itwould for an unused cartridge assembly 100. The use of an electricalmotor for one or more system functions also provides the opportunity tomonitor its operational status including the voltage and current levelssupplied to the motor as well as the number of revolutions that themotor has performed during a specific operation. Measurement of thesequantities during system operation can be used as a primary or secondarymethod for detecting potential or actual fault conditions. For example,the use of mechanical interlocks designed to block the loading procedurewhen the cartridge 100 is not properly configured can be coupled withsensors and logical circuits monitoring the motor to ensure properloading of the cartridge 100 into applicator 400. For example, theinteraction of the mechanical features described above that are designedto prevent the loading of cartridge 100 without a properly insertedreservoir or vessel 102 would result in increased load on the motordrive mechanism, resulting in a higher current draw. Detection of theelevated current draw by the motor would prompt the loading procedure tobe halted and a fault condition displayed to the user, for example onstimulator display 712 and/or applicator display 404.

Since it is possible that medicaments not intended for administration bythis method could be contained within reservoirs of similar size andconfiguration as that intended for use by this delivery method.Therefore, an additional aspect of the system is the incorporation ofone or more methods to ensure that the reservoir or vessel 101 insertedinto the cartridge 100 by the user is specifically, intended for usewith the device. The implementation of such features would reduce therisk that an incorrect medicament is administered to a given subject.Customarily, specific information in the user instructions and labelingof the medicament includes the route and method of administration.However, to further reduce the potential for user errors, theincorporation of mechanical, optical, and/or electrical features withinthe reservoir or vessel and device may be desirable. In one embodimentthe syringe may be designed to incorporate one or more unique mechanicalfeatures that are not present in other reservoirs which may be similarto those designed for use with this delivery method. For example, thereservoir or vessel may be specified to incorporate a rib or otherelongate feature on the flange or barrel of the reservoir. In thisembodiment, a corresponding mating feature would be included on thevessel interlock 120 such that the vessel interlock would be deactivatedonly if a reservoir with the appropriate mating feature were properlyinserted into the device. In the event that it is not feasible todirectly implement the feature in the design of the reservoir, analternative embodiment would include the placement of a secondarymechanical component on the reservoir that would be unique to reservoirsintended for use with the device. For example, a ring or otherappropriately configured feature designed to slide over the barrel ofthe reservoir may be used to “key” the reservoir for use with the deviceby mating with a corresponding feature in the outer cartridge 102, innercartridge 103, vessel interlock 120, vessel detection cap 118, or othersuitable feature within the cartridge 100. An additional embodiment acustom label of suitable size, color, and/or electrical conductivityapplied to a pre-determined location on the outer surface of reservoirsthat are intended for use with the device. Corresponding optical orelectrical sensors in applicator 400 would be configured to assess thepresence or absence of the label on the surface of the reservoir inorder to verify that the medicament inserted into the cartridge isintended for use with the device. The detection method would comprisethe use of optical or electrical signals applied to the surface of thelabel in order to assess its presence or absence. In this way,reservoirs containing medicaments not intended for use with the device(and therefore missing the relevant label) could be detected andexcluded from potential misuse.

A configuration of sensors is now described to perform the cartridgeloading and syringe detection determination described above, suchsensors further forming a portion of a cartridge loading subassemblywithin the application 400. In more detail, and referring in addition toFIGS. 6, 17B, and 18C, an exemplary way of detecting where the cartridgeassembly 100 is located is by use of a cartridge loading sensor 436 anda cartridge loaded sensor 438, which forms a portion of a loading drivesubassembly 454, the subassembly 454 further including cartridge guiderails 442 and a loading motor 444 which has a connection to a piniongear assembly 448 that pulls the cartridge assembly 100 into thecartridge assembly receiving volume 403 via racks 154 on the base of theouter cartridge 102. In more detail, when the cartridge loading sensor436 detects an initiating flag 172 on the cartridge assembly 100 (seeFIG. 6), the motor may be caused to initiate loading. When the cartridgeloaded sensor 438 detects the same flag, loading may be caused to cease.A continuing flag 174 may be employed that is required to be present forloading to continue.

The first “teeth” of the rack 154 can be configured to provide a tactilesensation (or audible or haptic) for the user when they are insertingthe cartridge assembly 100 into the cartridge assembly receiving volume403. Such configuration may include the shape and/or size of the rackteeth 154 as well as the amount of flexion permitted by theirpositioning in the outer cartridge. By adapting the rack teethimplementation, the desired degree of tactile feedback can be achievedwhile ensuring that it does not provide a significant force against theloading motor 444 from receiving and loading the cartridge assembly 100.

Referring in addition to FIG. 17A, and as noted above, the cartridgeassembly 100 is inserted into a cartridge assembly receiving volume 403within the applicator 400. While various ways may be employed to performthis insertion, one way that has been found particularly useful is byway of a pinion gear assembly 448 engaging racks 154 on the outercartridge 102. The use of more than one rack provides additionalstability, particularly torsional stability during the loading phase.Referring also to the insertion/injection drive assembly 456 of FIG.18A, in addition to drawing the cartridge assembly 100 within thecartridge assembly receiving volume 403, the insertion action furthercompresses an electrode/needle insertion spring 472 through a springcap/cartridge interface 470. The electrode/needle insertion spring 472is used as the primary driving force for the needle and electrodeinsertion during medicament delivery.

This hybrid motor/spring action provides numerous benefits. The motordrive is beneficial as it is highly controllable and allows thecartridge 100 to be loaded into the applicator 400 in a semi-automatedfashion with minimal input of mechanical force required by the user. Asdescribed above, the implementation of motor drive based mechanismsprovides monitoring of the operational status of the system. Forinstance, conveying the current draw and revolution count to the logicaland control circuitry in the system provides a supplementary method fordetection and diagnosis of potential fault conditions. Despite theseadvantages, in certain cases electric motors can be poorly adapted toexerting the necessary linear force over sufficiently brief time scalesthat is most desirable for effective transcutaneous deployment of arrayscomprising a plurality of elongate electrodes and, in selectedembodiments, hypodermic injection needles. In particular, thepenetration of dermal tissues is most consistently achieved by theapplication of a large linear force over a brief time scale. In someembodiments, the most favorable insertion characteristics are achievedwhen the penetrating electrodes, and when present, injection needlecontact the skin at higher velocity. This is because sharps travellingat increased velocity at the point of skin contact result in less tissuedeformation as they cut or penetrate the tissue. Therefore, in someembodiments, rapidly accelerating the sharps prior to contact with theskin is desired. In some embodiments, multiple electrodes and aninjection needle are frequently utilized. In another embodiment, thevelocity of the electrodes is at least 50 mm/second prior to contactwith the skin. In yet another embodiment, the velocity of the eletrodeis at least 500 mm/second prior to contact with the skin. Thisdeployment approach minimizes the discomfort perceived by the subjectduring the electrode penetration and is most favorable for maintaining aconsistent spatial relationship between the plurality of electrodes. Incontrast to electromechanical motors, spring driven mechanisms exhibit amore favorable discharge profile that is capable of imparting the rapidimpulse force to the electrodes and injection needle that is desirablefor transcutaneous electrode implantation. In particular, the forceexerted by a compression spring is at its peak at initial discharge.This is favorable for transcutaneous deployment where a high velocity atthe point of skin contact is favorable and, due to the viscoelasticityof skin tissue, the greatest force is required for penetration of theskin, particularly when contacting the skin with a plurality ofelectrodes and/or injection needles. In addition, a spring basedmechanism is capable of generating this force from a simple, durable,and compact form factor that can be readily integrated into a handhelddevice format. However, a disadvantage of spring based mechanisms isthat they typically require the input of substantial mechanical force bythe user in order to prime them for operation, especially for springswith high force constants and/or large displacements. The use of ahybrid motor and spring mechanism, as described in the presentdisclosure, achieves the desired deployment force characteristics whilebeing simple for the user to operate. While the hybrid motor and springmechanism is a preferred embodiment, depending on implementation, otherhybrid mechanisms incorporating two or more drive mechanisms wherein oneis capable of generating a rapid impulse force and the other is capableof priming the impulse force mechanism, e.g., a pump capable ofcompressing gas into a chamber and then discharging the compressed gasin order to apply an impulse force for deployment of the electrodes and,where applicable, hypodermic needle(s).

In any case, once loaded, the desired depth electrode deployment and/oragent administration is affirmatively selected by the physician or othermedicament administrator and the same transmitted to the applicator 400.Referring in addition to FIG. 13B, the depth may be selected by depthselection buttons 409 (or other equivalent interface such as a toggleswitch or sliding switch) and the result displayed on injection depthselection indicators 408 (or, again, other equivalent interface). Theavailable injection depths are conveyed to the user by appropriatelabeling of the applicator 400 and/or the cartridge 100. In someembodiments, any labeling regarding the injection depth is located onthe cartridge 100 and remains visible to the user following installationin the applicator 400. For example, the available injection depths maybe labeled on the upper surface of the alignment guide/splay shield 108.In order to avoid circumstances in which the user forgets or neglects toselect a depth of injection, it is preferable that the device does notallow the user to proceed with the administration procedure until suchaffirmative selection is made. This can be accomplished by theimplementation of appropriate control logic within the system such thatsubsequent elements of the device set up or usage are not accessibleuntil a valid depth selection has been entered by the user. In certainembodiments, when the user is prompted to affirmatively select theinjection depth, the controller display may convey to the userinformation regarding the proper methods for assessing the subject anddetermining the appropriate injection depth for the selectedadministration site.

Referring in addition to FIGS. 18A-18B, upon proper cartridge assemblyinsertion, the spring cap/cartridge interface 470 engages and alsopresses against the spring cover hole 471 and tabs 491. While a largespring force presses against the inner cartridge 103, the same isprevented from moving forward by engagement of a set of retaining posts488 against walls 494 of the outer cartridge 102. However, the forceexerted by 470 splays apart tabs 491 (which prevent inadvertent rotationof the lock ring during handling) thereby allowing rotation of thecartridge lock ring 114 by the motor drive mechanism. The rotation ofthe cartridge lock ring 114 causes rotation of the retaining posts 488.The retaining posts 488 can be rotated into either the channels forfirst depth 490 or the channels for second depth 492. The length of thechannels for first depth 490 correspond to one of the choices of depths,and the length of the channels for second depth 492 corresponds to theother, with one or the other depths being selected by the user usingbuttons 409. For example, the length of channels 490 may be in the rangeof 20-30 mm and the length of the channels 492 may be in the range of12-20 mm. The requirement of a user to affirmatively select a depthprovides yet another interlock. Without an affirmative selection, theapplicator may not allow activation/needle insertion. The rotation ofthe cartridge lock ring 114 is thus caused by a clockwise or acounterclockwise rotation directed by the applicator 400 according tothe dictates of the user. Requiring rotational motion of a set of postsinto such channels to achieve deployment of the electrodes and, ifpresent, injection needle greatly reduces the chances for accidentaldischarge, even upon violent jarring or falling.

In more detail, the rotation of the cartridge lock ring 114 istransmitted to the cartridge assembly 100 by the retaining posts 488,which are disposed upon proper cartridge assembly 100 insertion intoslots on an insertion mechanism gear drive ring 478. In FIG. 18A, theslots on the insertion mechanism gear drive ring 478 are disposed at 3o'clock and 9 o'clock positions. The insertion mechanism gear drive ring478 is mounted to a partial insertion gear ring 479, which is driven byan insertion mechanism drive motor 482. Driving the partial insertiongear ring 479 causes the insertion mechanism gear drive ring 478 torotate either clockwise or counter-clockwise. A flag 481 on a ring 480and accompanying insertion mechanism position sensor 483 are employed todetermine the position of the insertion mechanism gear drive ring 478,and is further used to accurately return the same to the 3 o'clock and 9o'clock positions when the applicator 400 is to be re-used with anothercartridge.

The above implementation provides various advantages. For example, theuser has to actively perform a step of selecting the depth beforeproceeding with the administration procedure. In so doing, the user hasto assess the proper depth of injection for the selected injection siteand prepare the site as noted in a guide or instructions for usedocument. As noted, the insertion mechanism, requiring rotational motionto deploy, is significantly hardened against accidental deployment dueto falling, dropping, jarring, and so on.

Variations are be understood by a person skilled in the art. Forexample, while two channels and two retaining posts are employed foreach depth, one channel and one retaining post may also be used. Varioustypes of motors and mechanisms may be employed for conveying therotational motion necessary to rotate the posts into the channels. Othervariations are also to be understood, including the use of solenoids andthe like. In lieu of the use of channels, motor driven deployment may beused to provide variable depths, which depths may be controlled simplyby how far the motor is controlled to drive the deployment. Preferably,in this context, the hybrid drive mechanism described would beconfigured such that the impulse discharge mechanism (e.g., the spring)is used for initial deployment through the dermis and then the motordrive mechanism is used to advance the electrodes to their desireddepth.

One or more interlocks may be in place which must be deactivated beforethe insertion mechanism gear drive ring 478 is caused to rotate,rotating retaining posts 488 into the channels.

First, a force detection interlock subsystem may be in place thatrequires the device to be applied to the subject at a force of greaterthan a predetermined amount prior to allowing the administrationprocedure to be initiated. This force may be measured by an appropriatemechanical or electromechanical system and the result fed back into thecontroller 700 and used as an interlock to prevent activation of thedevice where insufficient force is provided. In some embodiments, thecontroller 700 is capable of conveying the state of the force detectioninterlock to the user through visual, haptic, or auditory signals sothat a state of inadequate force can be corrected and the user mayproceed with administration. In the event that the user attempts toproceed with the administration in a state of inadequate force contact(e.g., by depressing a trigger 407 or other activation button),additional visual, haptic, or auditory signals may be provided by theapplicator 400 or controller 700 to notify the user that the interlockmust be deactivated prior to proceeding with administration.

The detection of the force applied to the subject can be accomplished ina number of ways. Referring to the particular implementation of FIGS. 4and 8A-8B, the alignment guide/splay shield 108 is equipped with a forcecontact pickup 128. The alignment guide/splay shield 108 can bemechanically biased in a distal direction (towards the subject) usingone or more force contact springs 126, of which four are shown in FIG.4. The force contact pickup 128 changes its position by virtue of theforce applied to the alignment guide/splay shield 108. In so doing, italso changes the state of an electrical circuit formed by the forcecontact pickup 128, a set of first pads 162, a set of second pads 164,and a flexible circuit 160. In particular, by testing for continuitybetween one or more pads 162 and one or more respective pads 164, it canbe determined how far backward or proximal the alignment guide/splayshield 108 has been moved by applied force, and thus if sufficient forceexists for proper delivery. The state of the circuit is read by theapplicator 400 using sensor contacts 434 (see FIG. 16). If sufficientforce is indicated, the force contact interlock is deactivated, allowingthe user to operate the device.

In one implementation, at the first contact point, the system may notregister that any particular force has been applied. At the secondcontact point, the system may register that it is at partial (but notsufficient) pressure. At the third contact point, the system mayregister that the prescribed level of pressure required to proceed withprocedure administration has been achieved, and the interlock maydeactivate. Preferably, the status of the force contact circuit isprovided to the user via the applicator display 404.

Variations are to be understood by a skilled person in the art. Forexample, the force contact interlock may form an electrical lock that isdeactivated either within the controller 700 or within the applicator400 itself. In another variation the force contact circuit may beconfigured to provide information regarding the status of the devicethroughout the procedure administration. In particular, the system mayinclude a feedback loop between the force contact circuit and thecontroller 700 wherein a reduction in the force applied by the userprecipitates the generation of a visual, haptic, or auditory signal bythe controller 700 and/or applicator 400 so that a state of reducedforce can be corrected. In a certain embodiment, a feedback loop existsbetween the force contact circuit and the controller 700 such that thedetection of a change in the applied force prompts the system toinitiate a check as to whether the electrodes remain properly deployedinto the tissue of the subject, e.g., via an impedance or resistancecheck between the electrodes. If the check is passed, then the procedureproceeds normally. In the event that the position of the electrodes isno longer acceptable then the procedure may be aborted and the usernotified of the state of the device through the generation of a visual,haptic, or auditory signal by the controller 700 and/or applicator 400.This feedback loop is of particular significance during the injection ofthe medicament. By monitoring the position of the device and the stateof the electrodes, the feedback loop between the force contact circuitand electrode resistance/impedance monitor, the system may detect if theelectrodes (and therefore the injection needle) are no longer in thesubject, allowing the system to halt operation of the injection drivemechanism 456 to cease depressing the reservoir plunger 484 andterminating the injection of the medicament. While this embodiment ismost readily implemented with a motor driven injection drive 456, othervariations can be implemented in the case of manually operated or springdrive mechanisms wherein the activation of mechanical interlocks may beused to halt actuation of the reservoir plunger following detection of afault condition. This feature may be particularly useful in stopping thetherapeutic agent from inadvertently spraying out into the environmentfor instance, where the applicator 400 is removed from the tissue of thesubject prior to completion of a medicament delivery. For medicaments ortherapeutic agents that are potentially hazardous for exposure to usersor the environment, such a design may avoid inadvertentdischarges/exposures.

Since the quantity of the dose delivered to the subject in a partialdose situation may be critical to inform the decision making of theclinician regarding further treatment, it is preferable that theinjection drive mechanism 456 include appropriate sensor and controlfeatures to determine the position of the injection drive plunger 484 atthe time the injection stroke was halted due to the detection of a faultcondition or other circumstance in which halting the injection stroke isnecessary. Preferably this is achieved through monitoring of therevolution count of the motor used to drive the injection drive plunger484, but other methods for monitoring the position of the injectiondrive plunger 484 including optical or electrical sensors may beemployed. Based on the known dimensions of the injection drive plunger484, the depth of insertion, and the reservoir 101, the use ofappropriate logic and control circuits can translate the position of theinjection drive plunger into an estimate of the volume of medicamentremaining in the syringe at the point at which the injection stroke wasterminated. Such information can be conveyed to the user via the display712.

In addition to providing a termination feature to terminate theinjection stroke in the event that a fault condition is detected, theuse of a motor injection drive 456 can also provide a supplementarydetector for detection of a fault condition or other operational issue.Specifically, the incorporation of appropriate measurement and logiccircuits to monitor the circuit drawn by the motor during the injectionstroke can be used to confirm that the injection has been administeredwithin defined specifications. Expected ranges for the current drawn bythe motor can be established for the various stages of the injectionstroke including the initial run up of the injection drive plunger 484before it contacts the plunger stopper 159, the initial interfacebetween the injection drive plunger 484 and the plunger stopper 159,actuation of plunger stopper 159 forward in the barrel of the reservoir101, and conclusion of the injection stroke as the plunger stopper 159contacts the end of the barrel of reservoir 101. By correlating theposition of the injection drive plunger 484 with the measured currentdrawn by the motor to the expected values during each phase of theinjection of the agent, the system is capable of identifying potentialfault conditions and conveying them to the user. For example, if theuser inadvertently inserted a reservoir 101 in which the plunger stopper159 had been partially actuated (and therefore did not contain the fullintended dose of medicament) into cartridge 100, the system could detectthat the expected increase in current drawn by the motor injection drive456 did not occur when the injection drive plunger 484 reached the outertolerance for plunger positioning. Under this circumstance the systemcould terminate the administration procedure and notify the user of thedetected fault. Additional fault conditions including (but not limitedto) faulty components in the applicator 400, breakage of the reservoir101, and/or a defective cartridge 100 would be potentially detectablevia this method.

Another ‘interlock’ to facilitate proper execution of the administrationprocedure is provided by the alignment guide/splay shield 108, which isillustrated in FIG. 9C. In this figure, the alignment guide/splay shield108 is shown with splay features 168 and a hole 170 defined therein forslidable movement of a stick shield 134. The stick shield 134 isillustrated in FIG. 9B, and electrode holes 167 are also illustrated.For transcutaneous insertion of electrodes and, where relevant,injection needles, having a consistent skin interface facilitatesdeployment of electrodes into the target tissue while maintaining thedesired spatial relationship between the members of the plurality. Inparticular, proper deployment is most consistently achieved when theskin is positioned perpendicularly to the direction of deployment. Inaddition, misalignment of the electrodes and injection needle arereduced when the skin is placed into tension in the orientationperpendicular to the direction of deployment. As can be seen, the splayshield 108 includes mechanical features including ribs and edges toengage with the skin and place it into tension perpendicular to thedirection of deployment. Combined with the force contact circuit pick upsystem described above which ensures a consistent force applied to theskin, the alignment guide/splay shield 108 ensures that the skin isoriented and placed under tension in the direction perpendicular to thedirection of electrode deployment. While this embodiment utilizesmechanical rib features to engage the skin at the device interface,numerous other designs and features could be utilized for engagementincluding the use of alternative materials with a high coefficient offriction when placed in contact with skin (e.g., rubber insets, adhesivepatches, and the like) or alternative mechanical features includingmolded textures, cut outs, and sawtooth features capable of placing theskin into tension.

As can be seen, the alignment guide/splay shield 108 has a preferentialdirection defined. As described above, spatial and temporalco-localization of the medicament distribution and electric fieldapplication are desirable. Notably, the inherent structural propertiesof skeletal muscle lead to a characteristic ellipsoid distributionpattern of intramuscular injections where the major axis of theellipsoid aligns with the striations of the muscle fibers. Forapplications involving intramuscular injections, it is thereforefavorable to arrange the electrodes to generate an ellipsoid electricfield profile. In order to ensure that the electrode array and resultantelectric field profile are properly oriented relative to the striationsof the target skeletal muscle, the use of an alignment guiding featureis of particular utility for intramuscular administration. The objectiveof the alignment guiding feature is to facilitate placement of thedevice such that the orientation of the electrode array is mostfavorable relative to the muscle striations and the resulting medicamentdistribution following injection. For an arm injection, the alignmentguide/splay shield 108 would desirably wrap around the arm horizontallylike an arm band. A similar orientation would be desired for the legwith the splay shield wrapping around the leg horizontally. It has beenfound that having the alignment guide/splay shield 108 configured inthis manner results in >98% accurate medicament deliveries by users evenin the absence of verbal instructions. The preferred direction shown andresulting skin placement is particularly useful for intramuscularinjections, because the diamond shaped array of electrodes (see thearray of distal ends of electrodes 137 in FIG. 9A, which roughly matchesthe shape of the stick shield 134 and its associated holes 167) is thenoriented properly to deliver a medicament and to cause electroporationof the medicament along the preferred muscular striation direction. Aprimary feature is that, when aligned properly, the skin should be flushwith the skin interface where the orifice is located, e.g., where theneedle emerges. In this way, a consistent interface to the skin isobtained.

Where the alignment relative to the target muscle is improper, the arcgenerally causes a visually evident gap, e.g., 2-5 mm, to occur betweenthe alignment guide/splay shield 108 and the skin. The visually evidentgap may be employed as a reminder to the user to reorient the applicator400. In addition, the applicator 400 can be less stable against the skinof the subject when it is improperly aligned. Alignment guide featureswherein the distance between edges of the “wings” of the feature are atleast 1.3 times the vertical height of the feature are preferable forfacilitating proper placement. In addition, in some cases the design ofthe feature is such that the tissue interface can be placed flushagainst the skin in the desired orientation while exhibiting at least a2 mm air gap when placed at a 90 degree angle relative to the desiredorientation.

Variations on the design of the alignment guide are to be understood bya skilled person in the art. For example, instead of an arc shapedalignment guide/splay shield 108, a “V” shaped one may be used. Othervariations are also to be understood with the key characteristic beingthat the device can be placed directly against the skin in the desiredorientation whereas a visually apparent gap between the tissue interfaceand the skin of the recipient of 2 mm or greater is present when thedevice is misaligned relative to the striations of the target muscle.

As noted above, the orientation of the alignment guide/splay shield 108is related in some implementations to the shape of the electrode array,because the diamond symmetry of the electrode array has a certaindistribution associated with it, and this distribution should bear acertain predetermined relationship to the shape of the alignmentguide/splay shield 108. Referring to FIGS. 9A-9B, the electrodes, andmore particularly the distal portions 137, are shown, which are four innumber. The electrodes are positioned in a diamond shaped array, whichmeans they have second order symmetry, i.e., are twofold symmetric, inthat they may be rotated and at two different positions appear the same.The electrodes extend in this array from holes 167 defined in the stickshield 134. The use of a diamond shaped array is particularly usefulbecause it is generally desired for intramuscular injections asdiscussed above. To reiterate, the second order symmetric array leads toa second order symmetric applied electric field. This type of appliedelectric field can have a preferred direction along the striations ofthe muscles if the alignment guide/splay shield 108 is orientedproperly. Thus the alignment guide/splay shield 108 and the second orderelectric field orientation work together in a synergistic fashion toaccomplish medicament propagation along the direction of musclestriation.

Broadly speaking, in a diamond shape, or other second-order symmetricshape, there is generally a major (long) axis and a minor (short) axis.The axes may bear a predetermined relationship with a preferred axis ofthe alignment guide/splay shield 108. For example, if the alignmentguide/splay shield 108 is thought of as having wings, with the arcuateshape of the wings encircling the arm, then a line segment connectingthe center of the wings may be perpendicular to the major axis of thediamond shaped array.

Variations are to be understood by a skilled person in the art. Forexample, while a diamond is one possible shape for an electrode array,another exemplary shape is a rectangle, which is also second-ordersymmetric. The electrodes may be placed into the appropriate positionsbut may be moved to within a predetermined or desired tolerance, e.g.,within 5%, 10%, and so on. Electrodes may be in various other shapes solong as they create a second order rotationally symmetrical electricfield.

In another variation, for non-intramuscular injections, other ordersymmetries may be used. For example, for skin, there is generally nopreferred direction of medicament propagation and so even a circulararray of electrodes may be employed for intradermal injections.

Other considerations of electrode arrays are as follows. The simplestarray configuration comprises two electrodes connected to the oppositepoles of the electrical energy source. As disclosed in U.S. Pat. Nos.5,873,549 and 6,041,252 (incorporated herein by reference in theirentirety), utilization of three or more simultaneously active electrodesarranged in a multi-element array can be used to increase target volumesof tissue and improve the uniformity in electrical field propagationwithin the target tissue. A wide range of geometrical electrodearrangements and activation patterns have been developed for electricfield application in tissue. These include electrodes arranged inlinear, rectangular, circular, or triangular configurations capable ofpropagating electrical fields in a volume of tissue of roughlyellipsoid, cuboid, cylindroid, or spheroid shape. Most commonly, theelectrodes are arranged parallel to one another and configured fortranscutaneous insertion in an orientation substantially perpendicularto the skin surface. In order to ensure that the target volume and shapeof tissue is affected by the application of electrical field, it isdesirable that the intended spatial relationship between each of theelectrodes within the array is achieved following transcutaneousinsertion. Specifically, unintended changes in the inter-electrodespacing should be avoided as they can cause changes in the magnitude ofthe electrical fields propagated within the target tissue, potentiallyleading to negative consequences for the safety and/or efficacy of theprocedure.

Another interlock involves use of an exterior cartridge cap 110. Inparticular, the alignment guide/splay shield 108 is covered while storedwith an exterior cartridge cap 110. The exterior cartridge cap 110 isconfigured to not just generally protect the distal end of the deviceuntil use but also to serve an interlock feature itself. Whileprotection of the distal end of the cartridge assembly 100 serves thepurpose of protecting the needle and electrodes from the environment, acommonly-encountered problem is that users often forget to remove suchcaps. One solution is to make the cap a bright color that is differentfrom the color(s) of the other components in cartridge 100, so as tonotify the user of its presence and thus remind the user to remove it.Another part of this solution is to include an extension or reminder tab190, as shown by the arcuate section adjacent a rectangular section, thearcuate section visible even when the cartridge assembly 100 is placedup against a subject. As this reminder tab 190 is visible, it can serveas a reminder to remove the exterior cartridge cap 110 even when theremainder of the exterior cartridge cap 110 is not visible.

Referring in more detail to FIGS. 10A-10B, the exterior cartridge cap110 includes an outer surface facing distally, towards the subject, andan inner surface facing the alignment guide/splay shield 108. On theinner surface are provided a number of hooks 176 which engage acorresponding wall 180 defined on the alignment guide/splay shield 108.The hooks hold the exterior cartridge cap 110 in place.

However, if the exterior cartridge cap 110 were inadvertently left inplace, and the applicator 400 pressed up against an insertion site withforce, the force of the alignment guide/splay shield 108 against theexterior cartridge cap 110 may tend to cause the exterior cartridge cap110 to “pop off” by being pushed away from its hooked position by thealignment guide/splay shield 108. However, chamfered surfaces 178 areprovided on the hooks 176 which tend to act against the stick shield 134when pressure is applied, causing the hooks 176 to splay outward,increasing their retaining force against the alignment guide/splayshield 108, and preventing the exterior cartridge cap 110 from poppingoff. In addition, the chamfered surface acts further against the stickshield, preventing the alignment guide/splay shield 108 from movingrelative to the stick shield 134. If the alignment guide/splay shield108 cannot move relative to the stick shield 134, the force detectioninterlock cannot be deactivated, as the force contact pickup 128 cannotmove to the third force contact point discussed above, where fullpressure is detected (or for that matter even to the second forcecontact point). The controller can provide a report when this happens tothe controller. For example, a user interface indication such as “Youneed to remove outer cartridge cap.” may be displayed, the same causedby detection of a trigger pull performed in the absence of adequateforce.

While certain interlocks have been described above, more or lessinterlocks may be provided in any given implementation. For example,other ways may be employed for force detection and use as triggeringsignals for interlocks. Other types of interlocks may also be employed,including trigger locks, safety switches, and the like. Yet other typesare to be understood by one of ordinary skill in the art, given thisteaching.

Once a depth of insertion is affirmatively selected by the user, and theexterior cartridge cap 110 is removed, and the proper force is detectedby the force interlock, activation of the trigger causes clockwise orcounterclockwise rotation of the cartridge lock ring 114, with thedirection of rotation dependent on the depth of insertion selected bythe user. The rotation causes the retaining posts 488 to move into thechannels of selected depth, which in turn causes the needle andelectrodes to deploy. In particular, the inner cartridge 103, cartridgebreech 112, reservoir 101, inner cartridge cap 104, needle hub 152,needle 105, electrodes 122, and associated elements to move forwardunder the influence of the electrode/needle insertion spring 472. In thepresent embodiment, these elements are rigidly connected to each otherand thus move forward as a unit.

To further minimize the risk of sharps injuries to the user, it ispreferable that the cartridge assembly also incorporates a mechanism forsheathing the electrodes and any injection needles following theirremoval from the recipients' tissue. This can be accomplished throughthe incorporation of a stick shield feature that houses the electrodesand injection needle (if present) prior to their use and then extendsover the electrodes and injection needle (if present) following theirdeployment and removal from the tissue of the subject. Commonly, thetissue contact interface comprises the distal surface of the shieldfeature. Although the use of manually operated shield features may beconsidered, preferably, the device incorporates a mechanism toautomatically extend the shield feature over the electrodes and furtherto engage a locking feature to maintain the shield feature in theextended state once it has been removed from the tissue of therecipient. Examples include a shield feature slidably engaged with thecartridge outer housing and operatively connected to a source of storedenergy, such as a spring, which slides the shield forward uponwithdrawal of the electrodes from the recipients' tissue. Alternatively,the mechanism can be contained within the applicator and configured toreverse the electrode deployment step, thereby retracting the electrodesand any associated injection needles behind the tissue contactinterface. This can be accomplished using simple electromechanicalmechanisms for linear motion such as motors or solenoids.

In a particular implementation, and referring back to FIG. 4 as well asto FIGS. 11A and 11C, the stick shield 134 is configured to stay inposition while the medicament delivery happens, but the movement forwardof the inner cartridge 103 and other associated components duringmedicament delivery causes compression of a stick shield spring 138.This compressed stick shield spring 138 then relaxes as the applicatoris removed from the subject, as the stick shield 134 is caused to moveforward when the applicator 400 is removed from the subject, coveringthe needle and electrodes, and protecting the subject and others againstthe uncovered sharps. Notably, this feature also prevents thevisualization of the sharps features during withdrawal, which canfacilitate acceptance from subjects experiencing anxiety related toneedles.

While the relaxed spring would otherwise be capable of recompressing,and in particular if the user moved the stick shield 134 proximally, itis prevented from doing so by the action of stick shield support arm132, which are mounted to the interior of the outer cartridge 102 andwhich serve a ratcheting function as the stick shield 134 moves forward.In particular, and referring to FIGS. 11A and 11C, stick shield supportarms 132 move over various sequential retaining walls, and can do soeasily when the stick shield 134 is moving distally. However, in theproximal direction, the stick shield 134 is prevented from movingbecause the stick shield support arms 132 abut the retaining walls inthis direction, in a ratcheting fashion, and do not allow passage.

An initial set of retaining walls 188 prevent proximal movement of thestick shield 134 prior to use of the cartridge assembly 100. A set offirst depth retaining walls 184 prevent proximal movement of the stickshield 134 after discharge at a first selected depth. A set of seconddepth retaining walls 186 prevent proximal movement of the stick shield134 after discharge at a second selected depth. The stick shield 134 isprevented from complete removal from the cartridge assembly 100 by theaction of the stick shield retaining hooks 182 acting against the innercartridge 103. In some embodiments, final lock out at final end of thestick shield.

Variations is to be understood by a skilled person in the art. Forexample, in one implementation the stick shield support arms 132 may beprovided by stamped metal support arms that interface with the outercartridge 102. In some embodiments, for instance, as shown in FIG. 9D,the support arm features are directly integrated as stick shieldretention features, for instance injection molded plastic features inthe outer cartridge cap 106 and/or alignment guide/splay shield 108. Thespecific material can be selected to achieve sufficient rigidity toprovide support to the elongate electrodes while retaining sufficientelasticity to prevent fracture of the component under load. Materialselection should also consider the intended method of sterilization forthe electrode array (e.g., gamma radiation, steam sterilization,ethylene oxide, or e-beam) to ensure that the features retain adequatematerial properties following sterilization. In an exemplary embodiment,the features, as implemented, should be capable of holding the stickshield 134 against proximal movement when at least 5 N, but morepreferably at least 15 N of force applied. Other ways of providing aratcheted function to prevent proximal movement of the stick shield mayalso be employed including a gear rack implemented on stick shield 134and a corresponding ratchet feature implemented in outer cartridge cap106.

Referring to FIG. 4, each elongate electrode 122 within the arraycomprises a distal portion 137 and a proximal portion 135 that are inconductive communication. The distal portion is configured for tissuepenetration and electric field propagation in tissue and the proximalportion is configured with a conductive contact region capable ofreliably achieving conductive communication with the electricalconnections contained within the applicator with a suitable source ofelectrical energy. The source of electrical energy can, by temporalvariation in the power applied to individual electrodes, cause aspatially and temporally varying electric field within the body of thesubject, generally confined to a volume around the region of medicamentdistribution, and the same can be used to advantage in electroporationtherapy.

The relevant characteristics of the electrodes include shape, diameter,tip profile, length, material composition, and conductivity, thespecifics of which are selected based on the intended application. Mostcommonly, the electrodes comprise electrically conductive elongate rodswith a curvilinear cross section with diameter 0.1-1.5 mm. Theelectrodes may be solid core or hollow. Most commonly hollow electrodesincorporate one or more orifices and an operative connection to a fluidreservoir, thereby allowing for the administration of the agent ofinterest or other associated medicaments including anesthetics,surfactants, proteins, adjuvants, or enhancers from the electrodeitself. Depending on the application, appropriate metallic electrodematerials include, but are not limited to titanium, gold, silver,aluminum, copper, tantalum, tungsten, molybdenum, tungsten, stainlesssteel, MP35N and alloys thereof. Electrodes may also be comprised ofelectrically conductive ceramics or plastics. To minimize unwantedelectrochemical reactions at the tissue electrode interface, it is oftendesirable that one or more of the electrodes are coated in a conductivematerial providing improved electrochemical stability compared to theelectrode material itself. Such coating materials include, but are notlimited to, platinum, platinum, iridium, palladium, osmium, gold,silver, titanium, and alloys thereof.

As described above, the tip of the distal portion is configured fortissue penetration. Common tip profiles include, but are not limited to,trocar, bevel, cone, blade, lance, and taper. For transcutaneouselectrode deployment, tip profiles with one or more cutting edges arepreferred. For certain applications where the penetrating tip profilemay be undesirable for generating the required electrical fields, thetip may be comprised of a non-conductive material fixed to the distaltip of the electrode or the penetrating tip may be covered in anadherent coating or tubing comprised of an biocompatible electricallyinsulating material such aspoly(p-xylylene) polymer, polyolefin,polyvinyl chloride, polyurethane, polyester, polyimide, silicone rubber,thermoplastic elastomer/rubber, ethylene tetrafluoroethylene,fluorinated ethylene propylene, and/or perfluoroalkoxy plastic.

Proximal to the penetrating tip are one or more conductive regionsconfigured for the propagation of electrical fields in tissue. In orderto confine the propagation of electrical fields to the target region oftissue, commonly, especially for subcutaneous and intramuscularadministration, at least a portion of the electrode length configuredfor penetration in the tissue is covered in an adherent coating ortubing comprised of an biocompatible electrically insulating materialsuch aspoly(p-xylylene) polymer, polyolefin, polyvinyl chloride,polyurethane, polyester, polyimide, silicone rubber, thermoplasticelastomer/rubber, ethylene tetrafluoroethylene, fluorinated ethylenepropylene, and/or perfluoroalkoxy plastic. In this way, electrodes maybe configured to only activate at a particular depth within the tissue.

Collectively, the number of electrodes and their inter-electrodedistance as well as the penetration depth of the electrodes and thelength of their conductive region define the volume of tissue in whichthe electric fields is applied. These parameters are selected based onthe specific objectives for the administration procedure, includingtarget tissue site as well as the volume, dose, and viscosity of theagent to be delivered as well as the variation in skin and subcutaneoustissue thickness in the intended recipient population. Generally, forintradermal administration in human recipients, arrays comprise 2-16electrodes of diameter 0.2-0.7 mm, an inter-electrode distance of 2-8mm, a depth of electrode penetration of 0.5-4 mm, and a conductivelength of 0.5-4 mm. Generally, for subcutaneous administration in humanrecipients, arrays comprise 2-8 electrodes of diameter 0.3-0.8 mm, aninter-electrode distance of 4-10 mm, a depth of electrode penetration of5-15 mm, and a conductive length of 2-8 mm. Generally for intramuscularadministration in human recipients, arrays comprise 2-8 electrodes ofdiameter 0.3-1.2 mm, with an inter-electrode distance of 4-12 mm, adepth of electrode penetration of 10-60 mm, and a conductive length of2-20 mm.

In order to avoid undesirable visualization and exposure to theelectrodes during the usage of the device, the cartridge assembly 100 ispreferably configured such that the electrodes 122 are recessed withinthe device prior to their insertion into the tissue of the recipient.Most commonly, this is accomplished by providing the outer housingstructure 102 slidably engaged with the electrode mount support, whichin one implementation comprises an inner cartridge 103 having seemsformed therein in which the electrodes are disposed. Prior to use, theelectrodes are recessed within the outer housing 102. During use, thesliding engagement of the electrode mount structure, e.g., the innercartridge 103, with the outer housing allows the electrodes 122 to slideforward relative to the distal tip of the outer housing 102, therebydeploying the electrodes 122 from the outer housing 102. The length ofthe sliding engagement between the electrode mount structure and theouter housing corresponds to the maximum desired depth of electrodepenetration for the given application.

As may be seen in FIG. 4, and the electrodes 122 have a proximal portion135 and a distal portion 137. The proximal portion is separated from thedistal portion by a shoulder or bend 139. The shoulder or bend 139 issecured by and between the inner cartridge cap 104 and the innercartridge 103. The shoulder or bend 139 provides a number of functions.First, while the electrodes at the distal end of the cartridge assembly100 are required to form an array of a certain size and shape asdescribed above, putting the electrodes 122 in the desired array sizeand shape at the proximal end of the cartridge assembly 100 isimpractical due to the presence of the reservoir 101. In other words,the electrodes 122 have to bend “out-of-the-way” to make room for thereservoir 101. In addition, having the bend, particularly when the bendis locked in place frictionally between the inner cartridge 103 and theinner cartridge cap 104, provides a surface for the electrodes 122 toabut against when the force of the needle and electrodes insertionrecoils in the distal direction as the electrodes 122 interact with thetissue during their deployment. The bend, can resistant to axialrotations, which is beneficial so that the electrodes do not exhibitsignificant torsional movement and rotate away from their electricalcontact pads 130 (described below). In addition, in contrast to priorart techniques in which multiple electrodes interfaced with axiallyseparated coaxial rings, requiring a different configuration for eachelectrode, the present system allows a common electrode type to be usedfor all four electrodes.

Systems and methods according to present principles provide for thepropagation of an electrical field in the skin, subcutaneous tissue,and/or skeletal muscle of a recipient which facilitates theintracellular delivery of a therapeutic agent within said recipient'stissue. In this aspect, the apparatus includes two or more elongateelectrodes 122 arranged in a predetermined spatial relationship andconfigured for deployment into the target tissue in which the agent ofinterest has been or is to be distributed. The desired enhancement inagent activity is contingent on achieving co-localization of the site ofagent distribution with the propagation of electrical fields ofsufficient magnitude to induce the desired physiological effects.Therefore it is desirable that the apparatus consistently achieveelectrode deployment to the target depth and with specifiedintraelectrode spacing. Specifically, this ensures that the electricalfields are propagated at the proper tissue site, and, since themagnitude of the electrical fields propagated within the tissue is afunction of the intraelectrode spacing, a safe and effective electricfield intensity. However, the variation in the thickness, density, andcomposition of skin and subcutaneous tissue between sites in a givenrecipient and across recipient populations can lead to significantvariation in electrode deployment characteristics. For example,recipients with increased thickness of skin are at increasedsusceptibility for electrode distortion and/or insufficient depth ofpenetration which can affect co-localization with the site of agentdistribution.

Systems and methods according to present principles further facilitateconsistent transcutaneous insertion of electrode arrays comprising 2-16electrodes of diameter 0.2-1.3 mm with an inter-electrode distance of2-12 mm, and a depth of electrode penetration of 0.5-60 mm in recipientswith skin of heterogeneous thickness, composition, and condition. Inorder to permit transcutaneous insertion, tissue penetrating electrodesare most commonly elongate and configured with a tissue penetrating tipand a tissue contact region in the distal portion and an electricalcontact region in the proximal portion. Given their elongateconfiguration, they are susceptible to bowing, bending, and/or buckling(collectively termed distortion) when subjected to the compressionforces generated during transcutaneous insertion into the recipient.Such distortions during electrode insertion are undesirable as they canlead to improper electrode insertion characterized by insufficient depthof penetration and/or excessive changes in intraelectrode spacing. Ofnote, humans and animals exhibit significant intra- and inter-speciesdifferences in the thickness, composition, and condition of skin, any ofwhich can have significant impact on the forces which the electrodes aresubjected to during transcutaneous insertion. In some embodiments,devices for transcutaneous insertion of elongate electrodes are designedto withstand the forces present under the most stringent conditions ofelectrode insertion that is to be encountered in the target populationof recipients. The occurrence of electrode distortion can be partiallymitigated by electrode material selection as well as reducing the lengthand increasing the diameter of the electrodes within the array. However,material selection may be constrained by issues of performance, cost,manufacturability, and biocompatibility. In addition, electrodes ofreduced length may preclude adequate coverage of a target populationwith heterogeneous tissue thickness while larger diameter electrodes areassociated with increased discomfort and tissue trauma. Thus, thepresent disclosure is designed to provide methods and apparatus tofacilitate the transcutaneous insertion of electrodes independent ofthese variables.

A first embodiment of the disclosure the subassembly cartridge housingthe electrode array incorporates one or more support dynamic supportmembers in physical contact with one or of the electrodes during tissueinsertion and configured to constrain movement of the electrodesperpendicular to the direction of insertion and maintain the desiredspatial relationship between the electrodes. For example, and referringto FIG. 12, an electrode support 124 is illustrated in which electrodeholes 192 are provided for electrodes and a needle hole 194 is providedfor passage of the needle. The tendency of the elongate electrodes todistort or buckle under load is exacerbated by any bending,eccentricity, or bowing of the electrode that may have been introducedduring manufacture or assembly. Thus, it is advantageous to employ adevice such as the electrode support 124 to constrain the electrodes toprevent, or correct, any bending, eccentricity, or bowing they mightexhibit at rest, and to prevent unwanted perpendicular motion of theelectrode as a result of the loading that occurs during deployment intotissue.

In the context of the present disclosure, a dynamic support member isdefined as a structural element which provides sliding engagement withthe elongate electrodes during insertion into the tissue of therecipient and which is configured to undergo a change in position, size,and/or conformation during electrode insertion in order to maintain thedesired spatial relationship of the electrodes as they are deployed tothe target tissue depth. Since the electrodes are subjected to thelargest loading forces at the initial contact with the skin, theengagement of the dynamic support member with the electrodes comprisingthe array is preferably affected prior to initial contact with thetissue of the recipient and to continue to provide support as theelectrodes deploy to the full depth of penetration. It is also favorablethat the dynamic support member be designed to provide support to theelectrodes and injection needle while minimizing losses in electrodepenetration force due to friction.

While the primary function of the dynamic support member is to maintainthe desired spatial relationship of the plurality of the electrodeswithin the array relative to one another and to the injection needle, itis also desirable for the design of the dynamic support member toinclude features capable of stabilizing the array as a whole. This ispreferably accomplished by providing additional structural supportfeatures which constrain lateral movement of the support member. In acertain embodiment, these support features are integrated into a sharpsprotection shield, which also serves to protect the user againstaccidental exposure to the electrodes and/or injection needle. Disclosedbelow are various embodiments of dynamic support members consistent withthe present disclosure.

One embodiment of the present disclosure, described above as electrodesupport 124, involves the use of a planar structure positionedperpendicularly relative to the elongate orientation of the electrodes.The planar structure is configured with one or more apertures 192 whichcorrespond to the positions of said electrodes in their specifiedspatial relationship. The size, shape, and position of the apertures areconfigured to allow the support structure to slide smoothly along theelongate length of the electrodes within the array while constrainingunwanted motion perpendicular to the direction of electrode deployment.Commonly, the apertures may be configured as holes or slots 192 in theplanar structure with adequate clearance for the electrode (at least 10%larger than the largest cross section of the electrode, including anycoatings or other adherent materials). However, if more substantialsupport is required for specific electrodes, one or more of theapertures may comprise tubular structures 196 arranged perpendicularlyto the planar structure. Apertures comprising such tubular structuresincrease the surface area contacting the electrode and thereby increasethe support provided to the elongate electrodes. The planar structuremay be made from any material with appropriate structuralcharacteristics including metal, polymer, ceramic, or compositematerials and may be formed, machined, molded, or produced with othermethods. To avoid unwanted electrical interactions with the electrodes,it is preferable that the interface between the electrodes and theplanar structure is not electrically conductive. The material andmanufacturing method should also be selected to minimize the amount offriction at the interface between the electrodes and the dynamic supportmember. Due to a number of factors including their low cost, ease ofmanufacturability, and favorable electrical properties, the electrodesupport is commonly made of a thermoplastic such as polycarbonate,polystyrene, polypropylene, acrylic, or polyethylene. The specificmaterial should be selected to achieve sufficient rigidity to providesupport to the elongate electrodes while retaining sufficient elasticityto prevent fracture of the component under load. Material selectionshould also consider the intended method of sterilization for theelectrode array (e.g., gamma radiation, steam sterilization, ethyleneoxide, or e-beam) to ensure that the dynamic support member iscompatible. The specific dimensions and design of the support structuredepend on the properties of the selected material. However, it isdesirable to minimize the dimensions of the support structure so that itdoes not excessively limit the distance that the electrodes can bedeployed or to interfere with other functional properties of the device.Rigid planar structures of 0.5 mm-2 mm thickness are typicallysufficient

Another embodiment of a dynamic support member is the use of acompression spring with apertures accommodating the electrodes andconstraining their lateral movement. The compression spring may be madefrom metal, polymer, or elastomeric materials, and may be formed,machined, molded, or produced with other methods. At rest, the spring isuncompressed or minimally compressed with the electrodes inserted intothe apertures along the spring's length. As the electrodes are deployed,the spring compresses in the direction of deployment, with the aperturesaccommodating the sliding movement of the electrodes perpendicular tothe spring coils. This embodiment is of particular utility when combinedwith a shield or sheath used to house the penetrating electrodes/needlesfollowing removal from the tissue site. In these embodiments, the forceimparted to the spring by the forward deployment of the electrodes canbe used to deploy a sheath or shield over the electrodes as the deviceis removed from the tissue.

In the implementation of FIG. 4, the stick shield spring 138 may be usedto partially support the electrode support 124, and in particular theradius of the spring may be configured to match (or be just slightlygreater than) the radius of the wall 198 of the electrode support 124.In this way, the electrode support 124 may be inserted into the middleof the stick shield spring 138 during use. The electrode support 124 maythen slide within the interior of the stick shield 134. By being placedin the center of the spring, the electrode support 124 naturallymaintains a position in the center of the spring, which provides adesired “halfway point” for support of the electrodes, roughly halfwaybetween their point of support at the inner cartridge cap 104 and theirpoint of penetration at the tissue interface.

Other spring-based electrode supports are contemplated. For example, aformed compression spring is positioned in the region of the electrodes,to provide adaptive electrode support. Formed compression springs may beshaped and proportioned to conform closely to the relative positions ofthe electrodes, in order to restrict their lateral motion. An optionalbiasing element may be positioned in conjunction with a formedcompression spring, and may serve to bias the electrodes outward againstformed compression spring. Formed compression springs may be made frommetal, polymer, or elastomer materials, and may be formed, machined,molded, or produced with other methods. The biasing element may be madefrom metal, polymer, or elastomer materials, and may be formed,machined, molded, or produced with other methods.

Electrode supports based on other mechanisms are also contemplated, forexample telescoping tubes. Telescoping tubes serve to support electrodesduring insertion into the subject. The telescoping tubes may be sized tomove freely relative to each other, or may be sized to move only when anaxial force is applied to them.

Other support structures are contemplated, for example supportstructures based on movable, flexible, or pivoting support members.Lateral support members may attach to the electrodes at optional hingefeatures. Lateral support members may be formed integrally with thestructure housing the electrodes or may be separate components attachedby conventional means (snaps, welding, adhesives, fasteners, etc.).

Another embodiment is the use of a compressible matrix material in whichthe electrodes are embedded. As the electrodes are deployed, thematerial compresses in the direction of deployment, providing lateralsupport along the direction of travel. Examples of compressible matrixmaterials include cellulose, foamed plastic or rubber polymers such asmicrocellular plastics, foamed silicone or foamed polychloroprene, orcarbon foam matrices. Since the materials are designed to contact theelectrodes and/or injection needle (if applicable), the materials shouldbe selected to be compatible with indirect tissue contact.

The above described structures thus support transcutaneous deployment ofa plurality of elongate electrodes at tissue depths of up to 60 mm whilemaintaining the desired spatial relationship among the plurality ofelectrodes and, in specific embodiments, the orifice of a hypodermicinjection needle. Such support members engage the plurality of elongateelectrodes during transcutaneous insertion, and constraining deflectionof the electrodes in one or more directions perpendicular to theirelongate orientation. Another aspect of the present disclosure providesmethods and apparatus for utilizing the application of biocompatiblelubricious compounds to the surfaces of the plurality of electrodes inorder to reduce the applied force required to achieve consistenttranscutaneous deployment of a plurality of elongate electrodes todepths of up to 60 mm. In an exemplary embodiment, biocompatiblesilicone compounds such as Dow Corning 360 Medical Fluid or Dow CorningMDX4-4159 can be applied by conventional spray or dip coating to theplurality of the electrodes comprising the array in order to improve theinsertion characteristics of the electrodes. The specific selection ofthe coating and application conditions, such as coating method andthickness depends on the number, size, composition, and tipconfiguration of the electrodes as well as the target tissue in whichthe electrodes are deployed.

Referring to FIGS. 4 and 7A-7B, a proximal portion 135 of each electrodemay be positioned on the exterior of the inner cartridge 103 of thecartridge assembly 100 (FIG. 7B). In this way, when the inner cartridge103 is slidably disposed within the outer cartridge 102 (FIG. 7A), theproximal portion 135 of each electrode contacts a correspondingelectrode contact 130, and in particular an outer cartridge interiorportion 133 of the electrode contact 130. The interior portion 133 isconfigured for power communication with the proximal portion 135 of eachelectrode. Due to the length of the proximal portions (a single proximalportion 135 pointed-to in FIG. 7A) of the electrodes, and the length ofthe outer cartridge interior portion 133, the electrical communicationcan be made at a number of locations along their continuous interface,no matter the longitudinal position of the inner cartridge with respectto the outer cartridge. Each electrode contact 130 further includes anouter cartridge exterior contact 131, configured for power communicationwith corresponding connections 496 on the applicator 400 (see FIG. 18C).Although not pointed to in the figures, there can a single electrodecontact that contacts one of the electrodes, when the electrodes areotherwise electrically coupled, or there can be an electrode contact 130corresponding to each of the electrodes, and additional correspondingfeatures such as interior portions 133 of the outer cartridgecorresponding with each electrode of the apparatus. Thus, despite beingreferred to in a plural or singular manner, several embodiments arecontemplated-aligning with singular and a plural meanings. Eachelectrode contact 130 is comprised of a conductive material sufficientto convey an electrical signal. In certain embodiments, the design andmaterial selection ensure that the contact provide for adequateengagement to ensure an electrically conductive interface with thecorresponding electrode over the range of expected manufacturingvariation in electrode and contact position while not inhibiting orinterfering with the forward travel of the electrodes 122 mounted on theinner cartridge 103. The design most also permit this engagement topersist when exposed to the expected storage conditions over the labeledshelf life of the product. In a certain embodiment, electrical contacts130 are made of stamped or formed metal with appropriate temper tofaciliate engagement with the electrode and may include coatings such asgold or copper to ensure the integrity of the electrical contacts andavoid corrosion. In addition to ensuring that electrical contact can bemaintained with the electrodes at a number of locations along theircontinuous interface, the incorporation of one or more electrode contactinto outer cartridge 102 in this configuration ensures that any wear dueto the sliding interaction between the electrodes 122 and the electrodecontact 130 occurs within the cartridge 100 designed for single use,thereby allowing for a static interface between the outer cartridgecontacts 131 and applicator electrical contacts 496 which minimizespotential mechanical wear on the electrode connections 496 of theapplicator designed for multiple uses. This configuration has thebenefit of extending the useful functional life of the multi-useapplicator.

Remaining portions of the applicator 400 are now described. Theseportions are generally those that are independent of operation with thecartridge assembly 100. Referring first to FIG. 13A, the applicator 400includes a handle 402 and a multi-conductor cable 406 designed to carrypower and control signals as well as the electrical signals to beapplied to the tissue. The cable 406 is generally terminated in aconnector with a corresponding connector interface in the controller700. The applicator 400 further includes a user interface 404, in whichaspects of the procedure may be viewed by the user, and in which theuser can direct the applicator to perform various functions, inparticular, depth selection. The applicator 400 further includes aprocedure activation trigger 407, which is used by the subject toinitiate the procedure.

Referring in addition to FIG. 13B, the applicator 400 includes aprocedure countdown timer 410, which informs the user of the remainingduration of the procedure, and further impliedly indicates to the userthat they should not remove the applicator 400 from the subject untilsuch time as the countdown trigger has counted down to zero. A powerindicator 418 is provided to indicate a satisfactory and poweredconnection with the controller 700. A procedure fault indicator 414 isprovided to indicate to the user if a fault has occurred, e.g., one ofthe interlocks described above has not been deactivated. An applicationplacement indicator 412 is provided to inform the user if a properpressure has been obtained against the tissue of the subject, allowingthe procedure to commence.

FIG. 14 indicates a number of structural components of the applicator400, including a connector 426 (not to scale) for connection to thecontroller 700, a top housing 420, side housings 422 and 424, and aninner protective shell 432. A front cap 430 is provided, along with anend cap 428. Various electromechanical subassemblies 450 are alsoprovided, several of which have been described above.

FIG. 15A illustrates a more detailed view of the applicator 400,indicating cartridge pressure sensor contacts 434 and subassemblies 452corresponding to the cartridge loading, electrode insertion, andinjection functions as well as the associated sensors.

FIG. 16 illustrates a more detailed view of the group of subassemblies452, including the loading drives subassemblies 454 and the cartridgeloading subassembly 456. The operation of the subassemblies has beendescribed above.

FIG. 17A illustrates a more detailed view of the loading drivesubassembly 454, the general to operation of which has been describedabove. Here it is noted that the loading is triggered by a flag on thecartridge assembly 100, and that detection of the flag leads to thesystem being triggered at switch 464. The loading drives subassembly ismounted to the applicator housing using brackets 466 and 468. The actionof the motor 444 is transmitted to the pinion gear assembly 448 by themotor drive shaft 462.

FIG. 17B illustrates a more detailed view of the insertion/injectiondrive assembly 456. Many of these components have been described above.Here it is noted that the operative components are mounted to theapplicator housing by a mounting bracket 476. Following insertion of theelectrodes 122 and the needle 105, the plunger of the needle 105 isdepressed by the injection drive plunger 484, whose action ejects themedicament from the orifice of the needle. The injection drive plungeris driven by an injection drive motor and gear assembly 486.

Generally the injection drive plunger, driven by the injection driveassembly 486, moves forward until such point at which it can no longermove forward, i.e., distally, indicating that it has reached the end ofeach stroke. This indication is generally given by the current used inthe injection drive motor 486 rising substantially, indicating that thereservoir plunger has reached the end of the reservoir and that theinjection has been completed. However, in some cases, the number ofturns of the motor may be employed to determine how much medicament hasbeen delivered. Such a feature could be used to support metered dosingof medicament or in order to notify the user in cases where the volumeof delivery was not within the expected total, e.g., where the fullvolume of reservoir 101 was expected to be injection, but based on theposition of the plunger rod, it was not emptied. These situations mayarise where the user failed to hold the applicator 400 against the bodyof the subject until the procedure was completed, e.g., until thecountdown timer had counted down to zero. As noted above, in amid-procedure timeframe, where the force against the subject is nolonger being detected, an impedance check may be performed to determineif the electrodes are still within the subject. If they are not, then itmay be presumed that the applicator was prematurely removed, and asignal may be sent to the injection drive motor 486 to cease injection,limiting the amount of medicament ejected outside of the subject.

Referring to FIG. 19, the controller system/assembly 700 can be seenincluding an electrical field controller/generator 750 and a handle 702and an applicator cradle 706. The controller may be configured for bothtable top as well as cart mounted use. In the cart mounted configurationit is the inclusion of a storage bin 704 is favorable. Details of thecontroller in the cart mounted configuration are shown in FIGS. 20A-20D,including wheel locks to secure the controller assembly against movementin an operational setting, a tray 710 for placing supplies includingsubject preparation supplies, reservoirs/vials/syringes, and so on. Anapplicator connector port 708 is illustrated to connect the applicator400 to the controller assembly 700. A display 712 displays status of anadministration procedure, particularly with regard to the IFU attached.

A cartridge eject button 714 is provided to cause ejection of thecartridge assembly 100 from the applicator 400. Menu navigation buttons716 allow navigation and manipulation of components as seen on thedisplay 712. A mute button 718 is provided to mute alerts or otheraudible indicators if desired. A power button 722 is provided to powerthe unit, and the same is activatable if the main power switch 726 (FIG.20D) has been turned on.

The display also includes a battery indicator 720, which provides anindication of battery level where a battery backup system is provided.Such a battery backup system may be included in the controller/generator750 to accommodate situations in which power loss prevents a main powersource from powering the unit. Such may also be employed as a backupwhere a procedure has been started under main power, but where a mainpower loss has been encountered. In this case, logic and controlcircuitry is implemented to provide for essentially seamless transitionfrom mains to battery power so that the procedure can be finished usingthe battery backup. It is favorable for the controller to includebattery monitoring circuitry that is capable of monitoring whether thebattery has sufficient charge to complete the procedure following lossof mains power. In some embodiments, the controller also includesdisplay to notify the user in the event that the current charge statusof the battery is not sufficient to complete the procedure in the eventof mains power loss.

Referring to FIG. 20D, in which a rear view of the controller 750 isillustrated, the same can be seen to include a USB port 724, a mainpower switch 726, and a main power input 728.

Referring to FIG. 21, in one method of use, as illustrated by theflowchart 800, the controller/generator 750 is powered and its programautomatically started (step 802). The applicator is connected (step804), and an indication or instruction to the user to perform thisaction may be displayed on the display screen 712, if the applicator hasnot already been connected. The system may perform a self test (step806), the self test not only ensuring proper operation of thecontroller/generator 750 but also ensuring correct connection of theapplicator 400 to the controller/generator 750.

The program may cause the display screen to provide instructions to theuser on preparation of the site of administration (step 808). This stepmay include ensuring that the correct medicament agent is beingdelivered, that the same is not expired, that contraindications havebeen reviewed, and that warnings/precautions have been followed.

The user then removes the vessel cap and inserts the reservoir 101 inthe cartridge assembly 100 (step 810). In some embodiments, the userexperiences an audible, tactile, or haptic click (step 811) indicatingproper placement of the reservoir in the cartridge assembly.

The user then inserts the cartridge assembly 100 into the applicator 400(step 816). An error status is then tested for (step 818), e.g., forproper reservoir placement, and if one is detected, the procedure isstopped, an error message is displayed, and the user is instructed totake remedial action. If the error state can be corrected, e.g., theuser has inserted the reservoir improperly but not engaged or closed thecartridge breech, then the user may be instructed to remove thecartridge and reinsert the reservoir properly (state 820). In somecases, the cartridge is automatically ejected, and in other cases theuser may have to push the “cartridge eject” button to accomplish thesame. In other error states, e.g., where the cartridge breech has beenclosed, the user may be instructed to use a new cartridge.

In any case, once the device set up is completed and a “no error” statehas been achieved, the user can proceed to administration of themedicament and electroporation therapy (step 822).

The primary function of the controller is to generate the electricalfields required to achieve the desired delivery of the medicament, tocontrol the operation of the system during set up and use, to monitorthe state of the system during set up and use, and to convey the stateof the system to the user during set up and use. In some embodiments,the controller is capable of providing recommendations and instructionsfor use of the device both in the context of user training as well asduring resolution of fault conditions during ordinary usage.

The controller system and controller method of operation may be fullyimplemented utilizing any number of computing devices includingmicroprocessors, microcontrollers, programmable logic controllers.Typically, instructions are laid out on computer readable media,generally non-transitory, and these instructions are sufficient to allowa processor in the computing device to implement the method of thepresent disclosure. The computer readable medium may be a hard drive orsolid state storage having instructions that, when run, are loaded intorandom access memory. Inputs to the application, e.g., from theplurality of users or from any one user, may be by any number ofappropriate computer input devices. For example, users may employ akeypad, keyboard, mouse, touchscreen, joystick, trackpad, other pointingdevice, or any other such computer input device to input data relevantto the calculations. Data may also be input by way of an inserted memorychip, hard drive, flash drives, flash memory, optical media, magneticmedia, or any other type of file—storing medium. The outputs may bedelivered to a user by way of a video graphics card or integratedgraphics chipset coupled to a display that maybe seen by a user.Alternatively, the system may output one or more formats of electronicdocument or a printer may be employed to output hard copies of theresults. Given this teaching, any number of other tangible outputs isalso be understood to be contemplated by the present disclosure. Forexample, outputs may be stored on a memory chip, hard drive, flashdrives, flash memory, optical media, magnetic media, or any other typeof output. It should also be noted that the present disclosure may beimplemented on any number of different types of computing devices, e.g.,personal computers, laptop computers, notebook computers, net bookcomputers, handheld computers, personal digital assistants, mobilephones, smart phones, tablet computers, and also on devices specificallydesigned for these purpose. In one implementation, a user of a smartphone or wi-fi—connected device downloads a copy of the application totheir device from a server using a wireless Internet connection. Anappropriate authentication procedure and secure transaction process mayprovide for payment to be made to the seller. The application maydownload over the mobile connection, or over the WiFi or other wirelessnetwork connection. The application may then be run by the user. Such anetworked system may provide a suitable computing environment for animplementation in which a plurality of users provide separate inputs tothe system and method. In the below system where control of anapplicator is contemplated, the plural inputs may allow plural users toinput relevant data at the same time.

TABLE OF ELEMENTS REF # PART 100 Cartridge assembly 101 Reservoir orvessel (which may be a pre-loaded or non -pre- loaded syringe) 102 Outercartridge, aka housing 103 Inner cartridge 104 Inner cartridge cap 105Needle 106 Outer cartridge cap 108 Alignment guide/splay feature 110Exterior (safety) cartridge cap 112 Cartridge breech 114 Cartridge lockring 116 Vessel detection spring 118 Vessel detection cap 120 Reservoiror vessel interlock, aka vessel insertion trigger, or vessel interlock122 Electrodes 124 Electrode support 126 Force contact springs 128 Forcecontact pickup 130 Electrode contact 131 Exterior Outer cartridgeelectrode portions for coupling to applicator 132 Stick shield supports133 Interior Outer cartridge electrode portions for coupling to innercartridge 134 Stick shield 135 Proximal Inner cartridge electrodeportions for coupling to outer cartridge 137 Distal Inner cartridgeelectrode portions for tissue insertion 138 Force contact flexiblecircuit 139 Electrode shoulder or bend 140 Reservoir or vessel loadingport or vessel loading port 142 Reservoir or vessel containment volumeor vessel receiver 144 & Reservoir or vessel lockout holes (1^(st) or2^(nd) set) or vessel 144′ lockout holes 146 Optical line of sight 148Insertion detector, e.g., emitter/collector IR sensor within applicator150 Inner cartridge containment volume 152 Needle hub 154 Rack 156Egress port 158 Vessel cap 159 Plunger stopper 160 Flexible circuit 162First set of pads 164 second set of pads 166 Stick Shield nubs 167 Stickshield holes 168 Splay feature 170 Alignment guide hole for stick shield172 Initiating flag 174 Continuing flag 176 Exterior cartridge cap hooks178 Exterior cartridge cap chamfer surfaces 180 Hook engaging wall ofalignment guide/splay shield 108 182 Stick shield retaining hooks 184First depth retaining wall 186 Second depth retaining wall 188 Initialor rest retaining wall 190 Reminder tab 192 Electrode support electrodeholes 194 Electrode support needle hole 196 Electrode support electrodehole support structure 198 Electrode support wall 400 Applicator 401Applicator cartridge assembly receiving port 402 Handle 403 Cartridgeassembly receiving volume, which is defined by a housing; or cartridgeassembly receiver 404 User interface 406 Multi-conductor cable 407Trigger 408 Injection depth selection indicator(s) 409 Injection depthselection button(s) (could be toggle or other forms in anotherimplementation) 410 Procedure countdown timer 412 Application placementindicator 414 Procedure fault indicator 416 Procedure complete indicator418 Power indicator 420 top housing 422 First side housing 424 Secondside housing 426 Electrical connector 428 End cap 430 Front cap 432Inner protective shell 433 Electrical contacts for motor drive 444 434Cartridge force sensor contacts 435 Connectors for switch 436 Cartridgeloading sensor 438 Cartridge loaded sensor 440 Guide or track 442Cartridge guide rails 444 Loading drive motor 446 Motor triggerconnector 448 Pinion gear assembly 450 Electromechanical subassemblies452 Cartridge loading, electrode insertion, and injection subassemblies454 Loading drive subassembly 456 Cartridge loading subassembly 462Motor drive shaft 464 System trigger switch 466 gear cover bracket 468Mounting bracket 470 Spring cover/cartridge interface 471 Spring coverhole 472 Electrodes/needle insertion spring 476 Mounting bracket 478Insertion mechanism gear drive ring 479 Insertion gear ring 480 Flagholder 481 Insertion mechanism flag 482 Insertion mechanism drive motor483 Insertion mechanism position sensor 484 Injection drive plunger 486Injection drive motor and gearing 488 Retaining posts (retainingfeature) 490 Channels for first depth 491 Lock tabs 492 Channels forsecond depth 494 Abutment wall 496 Applicator electroporation electrodecontact 700 Controller Assembly 702 Handle 704 Storage bin 706Applicator cradle 708 Applicator connector port 710 Tray 712 Displayscreen 714 Eject cartridge button 716 Menu navigation buttons 718 Mutebutton 720 Battery indicator 722 Power button 724 USB port 726 Mainpower switch 728 Main power port 750 Electrical Field Generator

EXAMPLES

The following example is provided for illustrative purposes only and notto limit the scope of the claims provided herein.

Example 1. Electroporation Mediated Intramuscular Administration ofNucleic Acid Based Biopharmaceuticals with TriGrid Delivery System(TDS-IM) Device

The intracellular delivery of nucleic acid sequences in the skeletalmuscle of the upper or lower limb can be enhanced with the use of anexemplary device, e.g. TriGrid Delivery System (TDS-IM) model II, asprovided herein. In some embodiments, the TDS-IM device is used inconjunction with agents approved for investigational use with the TDS-IMdevice. In an exemplary embodiment, the approved agent is nucleic acids,i.e., DNA or RNA. In some embodiments, the use of TDS-IM device isrestricted to a subject in need thereof.

To start up the system for administration, the main power of the deviceis connected to the stimulator and the system battery is adequatelycharged for use. The main power switch is turned on and the front panelpower button is depressed. The applicator is connected to the applicatorconnector. Proper connection of the applicator is confirmed by theillumination of the applicator power indicator. The start screen appearsonce the system completes all self-checks. The OK button is pressed toproceed with the procedure administration.

To insert a syringe into a TDS-IM cartridge, the syringe cap is removedfrom the syringe, and the syringe flange is align with the TDS-IMcartridge syringe loading port. The syringe should snap into place andbe fully seated in the TDS-IM cartridge. Once the syringe is loaded, theOK button is pressed on the pulse stimulator to continue. The cartridgecap should remain affixed to the cartridge until the cartridge is loadedinto the applicator.

To insert the syringe loaded cartridge into the applicator, thecartridge is aligned with the applicator with the cartridge syringeloading port facing upward. When the cartridge is inserted into theapplicator, and the cartridge is automatically drawn into its fullyloaded position in the applicator. Successful loading of the cartridgeis indicated in the stimulator. Once the cartridge is loaded, theapplicator is returned to its cradle, and an appropriate injection siteon the subject is selected. In some embodiments, the injection site forintramuscular nucleic acid delivery is medial deltoid muscle atapproximately three finger widths below the edge of acromion process(shoulder bone). In an exemplary embodiment, the injection depth atmedial deltoid is about 0.75″-1.25″ (19-30 mm). In some embodiments, theinjection site for intramuscular nucleic acid delivery is vastuslateralis muscle (outer thigh) at approximately the midpoint between thehip and the knee. In an exemplary embodiment, the injection depth atvastus lateralis is about 1.0″-1.5″ (25-38 mm). Once the injection siteis selected, the applicator depth selection button followed by theinjection depth selection button corresponding to the injectionsite/depth are pressed. In some embodiments, the injection depthselection indicator turns to solid illumination, confirming the selectedinjection depth. In some embodiments, the depth selection button on theright side corresponds to a deeper injection depth. In one embodiment,wherein initially selected injection site is to be changed, theselection button corresponding to the other injection depth is pressed,and the other injection depth is selected when the the select injectiondepth screen returns.

To start administration of an approved agent via TDS-IM device to thesubject, the cartridge cap is removed and discarded. The device isaligned with and firmly pressed against the target injection site. Whenthe device is firmly pressed against the target injection site, all fourbars of the applicator placement indicator illuminates, and theprocedure countdown timer illuminates with “8” seconds, indicating thetime remaining in the administration procedure. The applicator triggeris depressed for the agent to be administered while the pressure isconsistently maintained. When the procedure countdown timer reaches “0,”the electrical stimulation is delivered. Once the administrationprocedure is completed, the procedure complete indicator illuminates,and the device can be withdrawn from the injection site. The device maynot be withdrawn from the injection site until the procedure iscompleted or a procedure fault indicator illuminates. In someembodiments, wherein the device detects a problem during theadministration procedure, the device aborts the administration procedureand illuminates the procedure fault indicator. In an exemplaryembodiment, wherein the device aborts the administration procedure andthe device promptly is removed from the subject, the stimulator displayof the device provides further instructions.

To eject the cartridge from the applicator after completion of the agentadministration to the subject in need thereof, the eject button locatedon the stimulator is depressed. The applicator automatically advancesthe cartridge to the position where it can be manually removed from theapplicator. Once the cartridge stops moving, the sides of the cartridgeas indicated by arrows can be grasped for pulling the cartridge out ofthe applicator. After the cartridge is removed, completion of the fullinjection can be verified by inspecting the syringe plunger position. Toturn off the device, the applicator is placed in the holster, and thefront panel power button is pressed for 5 seconds.

While preferred embodiments of the present disclosure have been shownand described herein, it will be obvious to those skilled in the artthat such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the present disclosure. It should beunderstood that various alternatives to the embodiments describedherein, or combinations of one or more of these embodiments or aspectsdescribed therein may be employed in practicing the present disclosure.It is intended that the following claims define the scope of the presentdisclosure and that methods and structures within the scope of theseclaims and their equivalents be covered thereby.

What is claimed is:
 1. An apparatus for the controlled delivery of atherapeutic agent to a predetermined tissue site within a subjectcomprising: a cartridge assembly comprising an outer cartridge, an innercartridge, a vessel configured to contain the therapeutic agent, and aneedle hub, wherein the outer cartridge provides a vessel receiverconfigured to receive the vessel; an applicator comprising a cartridgeassembly receiver configured to receive the cartridge assembly or aportion thereof, and an insertion detector, wherein the insertiondetector is configured to sense loading of the vessel in the vesselreceiver; a vessel interlock, wherein the vessel interlock is configuredto lock out the apparatus from actuation until the vessel is loadedproperly in the vessel receiver; at least one injection orifice in fluidcommunication with the therapeutic agent when the agent is loaded in thevessel and through which the therapeutic agent is administered; aplurality of penetrating electrodes arranged with a predeterminedspatial relationship relative to the orifice; an electrical fieldgenerator configured to generate an electrical signal operativelyconnected to the electrodes; and a controlled source of energysufficient to transfer a predetermined amount of the therapeutic agentat a predetermined rate from the vessel through the orifice to thepredetermined site within the subject.
 2. The apparatus of claim 1,wherein the apparatus further comprises a needle.
 3. The apparatus ofclaim 1, wherein the electrodes are a plurality of elongate electrodes.4. The apparatus of claim 1, wherein the vessel interlock is configuredto prevent inadvertent actuation of cartridge function.
 5. The apparatusof any one of claims 1 to 4, wherein the vessel interlock comprises amechanical interlock.
 6. The apparatus of any one of claims 1 to 5,wherein the apparatus comprises a second interlock comprising a lightemitter/collector, a cartridge breech, a force interlock, an alignmentguide and a splay shield, a trigger lock, a safety switch, an exteriorcartridge cap or a combination thereof.
 7. The apparatus of any one ofclaims 5 to 6, wherein the mechanical interlock comprises tabs that aremoved from a first position to a second position by the vessel when thevessel is properly loaded, whereby when the tabs are in the secondposition, the device may be actuated.
 8. The apparatus of claim 7,wherein the vessel interlock further comprises at least one vessellockout hole.
 9. The apparatus of one of claims 6 to 8, wherein thecartridge breech provides an optical line of sight through a vessellockout hole.
 10. The apparatus of any one of claims 6 to 9, comprisinga vessel detection cap which engages the cartridge breech through avessel detection spring.
 11. The apparatus of claim 10, wherein thevessel detection spring is configured to push the reservoir intoengagement with the needle hub.
 12. The apparatus of any one of claims 1to 11, wherein the vessel interlock further comprises a tab extendingfrom a cartridge surface, and wherein the tab is configured to interactwith a corresponding detent feature located in the applicator such thatloading of the cartridge into the applicator is physically blockedunless the tab is deflected by a properly loaded vessel.
 13. Theapparatus of claim 6, wherein the first interlock comprises a splayshield, wherein said exterior cartridge cap comprises an inner surfaceproximal to said splay shield, and wherein said inner surface furthercomprises at least one hook capable of engaging a corresponding walldefined on said splay shield.
 14. The apparatus of claim 6, wherein theapparatus further comprise a third interlock.
 15. The apparatus of claim14, wherein the third interlock is a force interlock.
 16. The apparatusof claim 15, wherein the force interlock senses a force applied againstthe predetermined tissue site of the subject and prevents administrationof the therapeutic agent to the subject when insufficient force isapplied.
 17. The apparatus of any one of claims 15-16, wherein the forceinterlock further forms an electrical lock within the applicator. 18.The apparatus of any one of claims 15-17, wherein the force interlockfurther comprises at least one cartridge force sensor contact.
 19. Theapparatus of any one of claims 1-18, wherein the apparatus furthercomprises a key to the vessel, wherein the key the key mates to acorresponding feature within the cartridge assembly in order todeactivate at least one interlock.
 20. The apparatus of any one ofclaims 1-3, wherein the first interlock comprises a splay shield thatcomprises a rib and an edge configured to engage with the predeterminedtissue site of the subject and configured to place the apparatus intotension perpendicular to the direction of needle deployment foradministration of the therapeutic agent.
 21. The apparatus of any one ofclaims 5-20, wherein the first interlock further comprises a splayshield which comprises a force contact pick up.
 22. The apparatus ofclaim 21, wherein the force contact pick up comprises at least one firstpad, at least one second pad, and a flexible circuit.
 23. The apparatusof any one of claims 5-21, wherein the first interlock further comprisesa splay shield, and wherein said splay shield is mechanically biased byat least one force contact spring.
 24. The apparatus of any one ofclaims 1-23, wherein the cartridge assembly further comprises a stickshield.
 25. The apparatus of claim 24, wherein the stick shield furthercomprises a stick shield nub, a stick shield hole, and a stick shieldspring.
 26. The apparatus of claim 24, wherein the first interlockcomprises the splay shield that comprises at least one hole for slidablemovement of the stick shield.
 27. The apparatus of any one of claims24-26 further comprising at least one stick shield support to interfacewith the outer cartridge.
 28. The apparatus of claim 27, wherein thestick shield support is a stamped metal support arm.
 29. The apparatusof any one of claims 27-28 wherein the stick shield support moves overat least one retaining wall in a sequential order.
 30. The apparatus ofclaim 29, comprising a first retaining wall which can prevent proximalmovement of the stick shield in case of discharge of said apparatus at afirst selected depth and a second retaining wall which can preventproximal movement of the stick shield after discharge of said apparatusat a second selected depth in a subject.
 31. The apparatus of any one ofclaims 27-29, wherein the stick shield support is integrated as aninjection molded plastic feature of an outer cartridge cap.
 32. Theapparatus of any one of claims 27-31, wherein the stick shield supportabuts the stick shield and prevents the stick shield from moving in theproximal direction in a ratcheting fashion.
 33. The apparatus of any oneof claim 31-32, further comprising a gear rack implemented on the stickshield to reduce proximal movement.
 34. The apparatus of any one ofclaims 27-32, wherein the stick shield support prevents the stick shieldfrom moving in the proximal direction when at least 5 N of force isapplied.
 35. The apparatus of any one of claims 27-32, wherein the stickshield support prevents the stick shield from moving in the proximaldirection when at least 15 N of force is applied.
 36. The apparatus ofany one of claims 27-28 wherein the stick shield support is integratedas an injection molded plastic feature of the alignment guide and splayshield.
 37. The apparatus of any one of claims 1-36, wherein uponloading of the cartridge assembly into the applicator, the vessel movesforward to mate with the needle hub and contacts the cartridge to theneedle at the time of administration of the therapeutic agent.
 38. Theapparatus of any one of claims 1-37, wherein the inner cartridge movesin a slidable manner in relationship to the outer cartridge along acommon longitudinal axis.
 39. The apparatus of any one of claims 1-38,wherein the inner cartridge engages with an inner cartridge cap at adistal end, wherein the inner cartridge cap locks the electrodes inplace and provides a bearing surface for the stick shield.
 40. Theapparatus of any one of claims 1-39, wherein the apparatus furthercomprises a sensor.
 41. The apparatus of claim 40, wherein the sensor isselected from the group consisting of a cartridge loading sensor, acartridge loaded sensor, a cartridge force sensor, a needle insertionmechanism position sensor, a vessel insertion detector, an opticaldetector, and an electrical sensor.
 42. The apparatus of any one ofclaims 1-40, comprising a loading drive subassembly comprising acartridge loading sensor and a cartridge loaded sensor.
 43. Theapparatus of claim 42, wherein the loading drive subassembly furthercomprises at least one cartridge guide rail and a loading motor.
 44. Theapparatus of any one of claims 42-43, wherein the loading drivesubassembly further comprises a connection to a pinion gear assemblypulling the cartridge assembly into the cartridge assembly receiver viaa rack on a base of the outer cartridge.
 45. The apparatus of claim 44,wherein the pinion gear assembly engages the rack on the outercartridge.
 46. The apparatus of any one of claims 44-45, wherein therack comprises at least a first rack tooth.
 47. The apparatus of claim46, wherein the first rack tooth provides a tactile sensation when thecartridge assembly is inserted into the cartridge assembly receivingvolume.
 48. The apparatus of any one of claims 46-47, wherein the firstrack tooth provides torsional stability.
 49. The apparatus of any one ofclaims 41-48, wherein the cartridge loading sensor detects an initiatingflag on the cartridge assembly to initiate loading.
 50. The apparatus ofany one of claims 41-48, wherein the cartridge loaded sensor detects aninitiating flag on the cartridge assembly to cease loading.
 51. Theapparatus of any one of claims 1-50, wherein the apparatus furthercomprises a continuing flag for the cartridge loading to continue. 52.The apparatus of any one of claims 1-51, comprising a vessel insertiondetector that comprises a light emitter/collector IR sensor.
 53. Theapparatus of any one of claims 40-52, wherein the sensor detects avessel label and verifies identity of the therapeutic agent containedtherein.
 54. An apparatus for the controlled delivery of a therapeuticagent to a predetermined tissue site within a subject comprising: acartridge assembly comprising a housing, a vessel configured to containthe therapeutic agent, and a needle hub, wherein the housing comprises avessel receiver configured to receive the vessel; an applicatorcomprising a cartridge assembly receiver, and a vessel insertiondetector, wherein the vessel insertion detector is configured to senseloading of the vessel in the vessel receiver; and at least one injectionorifice of an injection needle through which the therapeutic agent isadministered; a plurality of penetrating electrodes arranged with apredetermined spatial relationship relative to said injection orifice;an electrode support comprising a plurality of apertures correspondingto the predetermined special relationship of the electrodes and throughwhich the electrodes extend, wherein the electrode support structureprevents inadvertent perpendicular motion of the electrodes relative tothe direction of electrode deployment; an electrical field generatorconfigured to generate an electrical signal that is operativelyconnected to the electrodes; and a controlled source of energysufficient to transfer a predetermined amount of the therapeutic agentat a predetermined rate from the reservoir through the orifice to thepredetermined site within the subject.
 55. The apparatus of claim 54,wherein the apparatus further comprises a needle.
 56. The apparatus ofclaim 54, wherein the apparatus further comprises an electrode insertionspring or a needle insertion spring.
 57. The apparatus of claim 54,wherein the proximal portion of the electrode is separated from thedistal portion of the electrode by an electrode shoulder or an electrodebend.
 58. The apparatus of claim 54, wherein the cartridge comprises anouter cartridge which provides an operative connection between aconductive contact region located on the distal region of the electrodesand the controlled source of energy when the electrodes are deployedinto the predetermined tissue site within the subject.
 59. The apparatusof any one of claims 54-55, wherein the electrode support comprises aneedle hole positioned to allow for passage of the injection needletherethrough.
 60. The apparatus of any one of claims 54-59, wherein theelectrode support comprises a planar structure positionedperpendicularly relative to the elongate orientation of the electrodes.61. The apparatus of claim 60, wherein the planar structure furthercomprises an aperture which is a hole or a slot configured to allowpassage of the electrode therethrough to the predetermined tissue site.62. The apparatus of any one of claims 60-61, wherein the aperturecomprises at least one tubular structure arranged perpendicularly to theplanar structure.
 63. The apparatus of any one of claims 60-62, whereinthe planar structure is oriented perpendicular to the longitudinal axesof the electrodes.
 64. The apparatus of any one of claims 54-63, whereinthe electrode support is an adaptive electrode support.
 65. Theapparatus of claim 64, wherein the adaptive electrode support is acompression spring.
 66. The apparatus of claim 65 wherein thecompression spring is made from a metal, a polymer or an elastomericmaterial.
 67. The apparatus of any one of claims 54-66 wherein theelectrode support comprises at least one telescoping tube.
 68. Theapparatus of any one of claims 54-67, wherein the electrode supportfurther comprises a stick shield spring.
 69. The apparatus of claim 54wherein the electrode support further comprises at least one lateralsupport member attached to the electrodes with at least one optionalhinge feature.
 70. The apparatus of any one of claims 54-69, wherein theelectrode support comprises a metal, a polymer, a ceramic, a composite,or a compressible matrix material.
 71. The apparatus of claim 70,wherein the compressible matrix material is selected from the groupconsisting of a cellulose, a foamed plastic, a rubber polymer, amicrocellular plastic, foamed silicon, foamed polychloroprene, carbonfoam matrix.
 72. The apparatus of any one of claims 54-71, wherein theelectrode support is made from an unconducive material.
 73. Theapparatus of any one of claims 54-72, wherein the electrode support ismade of a thermoplastic material.
 74. The apparatus of claim 73, whereinthe thermoplastic material is selected from the group consisting of apolycarbonate, polystyrene, polypropylene, an acrylic, or apolyethylene.
 75. The apparatus of any one of claims 54-74 wherein theelectrode support supports transcutaneous deployment of the electrodeand maintains at tissue depths up to 60 mm.
 76. The apparatus of any oneof claims 54-75 wherein an electrode proximal portion of each electrodeis coupled to or contacts an electrode contact, wherein each electrodeis positioned on the exterior of the inner cartridge of the cartridgeassembly, wherein the electrode contact is configured for powercommunication with corresponding connections on the applicator.
 77. Theapparatus of claim 76, wherein the electrode contact further comprisesan outer cartridge exterior contact.
 78. The apparatus of any one ofclaims 76-77, wherein the electrode contact provides an electricallyconductive interface with corresponding electrodes while not interferingwith forward travel of the electrodes mounted on the inner cartridge.79. The apparatus of any one of claims 1-78, wherein the cartridgeassembly further comprises a vessel loading port.
 80. The apparatus ofany one of claims 1-78, comprising an outer cartridge, said outercartridge comprising an inner cartridge containment volume.
 81. Theapparatus of any one of claims 1-78, wherein the applicator furthercomprises an injection drive assembly, wherein the injection driveassembly mates with the cartridge assembly.
 82. The apparatus of any oneof claims 1-78, wherein the applicator further comprises a an applicatorcartridge assembly receiving port.
 83. The apparatus of any one ofclaims 1-78, wherein the applicator further comprises a a procedureactivation trigger.
 84. The apparatus of any one of claims 1-78, whereinthe applicator further comprises a connector for connection to thecontroller, a top housing, a side housing, and an inner protectiveshell.
 85. The apparatus of any one of claims 1-78, wherein the vesselfurther comprises a vessel cap.
 86. The apparatus of any one of claims1-78, wherein the apparatus further comprises an egress port.
 87. Theapparatus of any one of claims 1-78, wherein the apparatus furthercomprises a plunger stopper.
 88. The apparatus of any one of claims1-78, wherein the apparatus further comprises a multiconductor cable.89. The apparatus of any one of claims 1-78, wherein the apparatusfurther comprises an exterior cartridge cap chamfer surface.
 90. Theapparatus of any one of claims 1-78, wherein the apparatus furthercomprises an exterior cartridge cap hook.
 91. The apparatus of any oneof claims 1-78, wherein the apparatus further comprises a main powerport.
 92. The apparatus of any one of claims 1-78, wherein the apparatusfurther comprises a main power switch, a power button, and a powerindicator.
 93. The apparatus of any one of claims 1-78, wherein theapparatus further comprises a at least one connector for switch.
 94. Theapparatus of any one of claims 1-78, wherein the apparatus furthercomprises an USB port.
 95. The apparatus of any one of claims 1-78,wherein the apparatus further comprises a reminder tab.
 96. Theapparatus of any one of claims 1-78, wherein the apparatus furthercomprises a battery indicator.
 97. The apparatus of any one of claims1-78, wherein the apparatus further comprises a mute button.
 98. Theapparatus of any one of claims 1-78, wherein the apparatus furthercomprises at least one menu navigation button.
 99. The apparatus of anyone of claims 1-78, wherein the apparatus further comprises an ejectcartridge button.
 100. The apparatus of any one of claims 1-78, whereinthe apparatus further comprises a display screen.
 101. The apparatus ofany one of claims 1-78, wherein the apparatus further comprises a tray.102. The apparatus of any one of claims 1-78, wherein the apparatusfurther comprises an applicator connector port
 103. The apparatus of anyone of claims 1-78, wherein the apparatus further comprises anapplicator cradle.
 104. The apparatus of any one of claims 1-78, whereinthe apparatus further comprises a cradle.
 105. The apparatus of any oneof claims 1-78, wherein the apparatus further comprises a storage bin.106. The apparatus of any one of claims 1-78, wherein the apparatusfurther comprises a handle.
 107. The apparatus of any one of claims1-78, wherein the apparatus further comprises a abutment wall.
 108. Theapparatus of any one of claims 1-78, wherein the apparatus furthercomprises at least one applicator electroporation electrode contact.109. The apparatus of any one of claims 1-78, wherein the apparatusfurther comprises at least one electrical connector.
 110. The apparatusof any one of claims 1-78, wherein the apparatus further comprises acartridge loading subassembly.
 111. The apparatus of any one of claims1-78, wherein the apparatus further comprises a motor drive and at leastone electrical contact for motor drive.
 112. The apparatus of any one ofclaims 1-78, wherein the apparatus further comprises a loading drivemotor.
 113. The apparatus of any one of claims 1-78, wherein theapparatus further comprises a motor trigger connector.
 114. Theapparatus of any one of claims 1-78, wherein the apparatus furthercomprises a motor drive shaft.
 115. The apparatus of any one of claims1-78, wherein the apparatus further comprises at least oneelectromechanical subassembly.
 116. The apparatus of any one of claims1-78, wherein the apparatus further comprises at least one cartridgeloading, electrode insertion, and injection subassembly.
 117. Theapparatus of any one of claims 1-78, wherein the apparatus furthercomprises at least one injection depth selection button and an injectiondepth selection indicator.
 118. The apparatus of any one of claims 1-78,wherein the apparatus further comprises a procedure countdown timer.119. The apparatus of any one of claims 1-78, wherein the apparatusfurther comprises at least one gear cover bracket and at least onemounting bracket.
 120. The apparatus of any one of claims 1-78, whereinthe apparatus further comprises a system trigger switch.
 121. Theapparatus of any one of claims 1-78, wherein the apparatus furthercomprises a system trigger switch.
 122. The apparatus of any one ofclaims 1-78, wherein the apparatus further comprises a procedure faultindicator and a procedure complete indicator.
 123. The apparatus of anyone of claims 1-78, wherein the apparatus further comprises a depthselection button.
 124. The apparatus of claim 123, wherein the depthselection button is selected from the group consisting of a toggle, aswitch, and a sliding switch.
 125. The apparatus of any one of claims1-78, wherein the apparatus further comprises a plurality of channel anda plurality of retaining post.
 126. The apparatus of any one of claims1-78, wherein the apparatus further comprises an insertion mechanismgear drive ring and an insertion gear ring.
 127. The apparatus of claim126, wherein rotation of the insertion mechanism gear ring rotates theretaining post into the channel.
 128. The apparatus of any one of claims1-127, wherein the apparatus further comprises an insertion mechanismflag, an insertion mechanism drive motor, an insertion mechanismposition sensor, an injection drive plunger, an injection drive motor,or an injection drive gearing.
 129. The apparatus of any one of claims1-127, wherein the apparatus further comprises a cartridge lock ring.130. The apparatus of claim 129, wherein the rotation of the cartridgelock ring rotates the retaining posts.
 131. The apparatus of any one ofclaims 1-130, wherein the cartridge assembly is for single use.
 132. Theapparatus of any one of claims 1-130, wherein the applicator is formultiple uses.
 133. The apparatus of any one of claims 1-132, whereinthe applicator further comprises a top housing, a side housing, an innerprotective shell, a front cap, and an end cap.
 134. The apparatus of anyone of claims 1-133, wherein the applicator further comprises a userinterface, a procedure activation trigger, a procedure countdown timer,a procedure fault indicator, or an application placement indicator. 135.The apparatus of any one of claims 1-134 wherein the apparatus furthercomprises a controller.
 136. The apparatus of claim 135, wherein thecontroller comprises a controller assembly.
 137. The apparatus of anyone of claims 1 to 135, wherein applicator further comprises a connectorfor connection to the controller.
 138. The apparatus of any one ofclaims 135 to 137, wherein the controller further comprises anelectrical field controller.
 139. The apparatus of claims 1-138, whereinthe penetrating electrodes and/or the injection needle come in contactwith the predetermined tissue site with velocity of at least 50mm/second.
 140. The apparatus of claims 1 to 139, wherein thepenetrating electrodes and/or the injection needle come in contact withthe predetermined tissue site with velocity of at least 500 mm/second.141. The apparatus of any one of claims 1 to 140, wherein thetherapeutic agent is a nucleic acid.
 142. The apparatus of claim 141,wherein the nucleic acid is DNA.
 143. The apparatus of any one of claims1-142, wherein the predetermined tissue site is located in a skeletalmuscle of the subject
 144. The apparatus of claim 143, wherein theskeletal muscle of the subject is medial deltoid muscle.
 145. Theapparatus of claim 143, wherein the skeletal muscle of the subject isvastus lateralis muscle.
 146. The apparatus of claim 144, wherein aninjection depth at medial deltoid muscle is about 19-30 mm.
 147. Theapparatus of claim 145, wherein an injection depth at vastus lateralismuscle is about 25-38 mm.
 148. The apparatus of any one of claims 1-147comprising a hybrid motor/spring mechanism for contacting at least oneof said injection orifice or said plurality of electrodes with saidpredetermined tissue site.
 149. The apparatus of claim 148, furthercomprising a measurement and logic circuit to monitor the current usageof motor during the injection stroke and compare said usage to apredetermined standard.
 150. The apparatus of any one of claims 1-149,further comprising a controller and a force contact circuit wherein afeedback loop exists between said controller and said force contactcircuit such that upon insertion of said plurality of electrodes in saidpredetermined tissue site, detection of a change in an applied forceprompts initiation of a check as to whether the electrodes remainproperly deployed in said predetermined tissue site.
 151. The apparatusof any one of claims 1-150 wherein said plurality of electrodes aredeployed by rotational motion.
 152. The apparatus of claim 151, whereinthe therapeutic agent is discharged by deployment of a needle byrotational motion.
 153. A method of providing a therapeutic agent to apredetermined tissue site in a subject in need thereof, comprisingcontacting said subject with an apparatus of any one of claims 1-152.154. A system for providing a therapeutic agent to a predeterminedtissue site in a subject in need thereof, comprising an apparatus of anyone of claims 1-152.